Physiology Flashcards

Question

**Intravascular Fluid** 1. % of total body mass 2. % of total fluid 3. volume

Answer 1

**Intravascular Fluid** * 4.5% total body mass * 7.5% total fluid * 3.15L

Answer 2

**Blood Volume** * 7% of total body mass * 12% of total fluid * 5L

Answer 3

**Interstitial Fluid** * 12% of total body mass * 20% of total fluid * 8.4L

Answer 4

1050ml (1.5% total body mass) | Fluid formed by the secretory activity of cells

Answer 5

* synovial fluid * CSF * aqueous humour * bile * bowel contents * peritoneal fluid * pleural fluid * urine in the bladder

Answer 6

The rate of diffusion is proportional to concentration and surface area

Answer 7

* The surface area of all the cells that interfere with the extracellular fluid is huge * The concentration of water molecules is very high * The lipid bilayer in very thin

Answer 8

Because diffusion rate in inversely proportional to the thickness of the membrane

Answer 9

The presence of embedded proteins and lipids which change the membrane properties (aquaporins)

Answer 10

The equilibrium of osmolality of the compartments, therefore the most important osmotic agent is extracellular sodium, which is under tight regulation

Answer 11

* it acts as a solvent * its presence is essential for enzyme function * it acts as a reagant itself

Answer 12

* The first Gibbs-Donnan effect (passive), which is established by the equilibration of diffusable and non-diffusable solvents on either side of the cell membrane * The second Gibbs-Donnan effect (active), which is maintained by the actions of the Na+/K+ATPase

Answer 13

The unequal distribution of permeant charged ions of either side of a semi-permeable membrane, which occurs in the presence of impermeant charged ions | Equilibrium - both sides of the membrane will have equal charged ions

Answer 14

60mmol/Kg 70kg man - 4200mmol ECF - 50% total sodium ICF - 5% total sodium

Answer 15

Due to the Gibbs-Donnan effect

Answer 16

By the action of the Na+/K+ATPase, which exchanged 3 sodium atoms for every two potassium

Answer 17

40mmol/Kg 70kg man - 2800mmol ICF - 90% ECF - 2% Bone - 8%

Answer 18

* It moves freely between intravascular and interstitial fluid due to low concentrations * Na+/K+ATPase exchanges three sodium ions out of the cell and two potassium ions into the cell

Answer 19

360mmol/kg 70kg man - 25mol >99% is stored in bone ECF - 30mmol Intracellular calcium is minimal but it is an important secondary messenger

Answer 20

* it moves freely between interstital and intravascular fluid * it is actively transported by ATP-powered pumps, which is important because it is a second messenger

Answer 21

15mmol/Kg 70kg male - 1050mmol 60% is in bone 39% is intracellular 1% is ECF

Answer 22

* magnesium moves freely between ECF * magnesium enters cells freely * intracellular magnesium is bound to ATP, cell wall lipids and many various enzymes

Answer 23

The voltage (charge) difference between the extracellular and intracellular fluid when the cell is at rest

Answer 24

* **chemical gradients created by ion transport pumps** eg potassium, sodium, calcium * **selective membrane permeability** - volatage-gated ion pumps * **electrical gradients** - generated because potassium leak (via K2P channels) from the intracellular fluid creates a negative intracellular charge, attracting potassium back into cells (opposite to chemical gradient) * **electrochemical equilibrium develops** when chemical and electrical gradients are equal (**Nernst equation**)

Answer 25

The transmembrane potential difference generated when that ion is at electrochemical equilibrium

Answer 26

The net charge of the intracellular side of the cell is -70 - -90mV

Answer 27

If you account the below as constants you will get: V*k* = -60mV log10 x (K*in* - K*out*)

Answer 28

K+ -94mV **Cl- -80mV** Na+ +60mV **Ca2+ +130mV**

Answer 29

Most things are pretty constant so it basically equals out as the Nernst equation (just potassium)

Answer 30

The transmembrane potential required to produce depolarisation of the membrane = -55mV

Answer 31

The finding that a subthreshold stimulus will produce no response, whereas a suprathreshold stimuli will produce an identical and maximal response.

Answer 32

**Depolarisation** occurs as the result of voltage-gated sodium channels opening when the threshold potential is reached - The result is an influx of sodium ions into the cell - This rapidly depolarises the membrane (.5-1.0msec)

Answer 33

**Repolarisation** occurs due to potassium channel opening and sodium channels closing * Sodium channels enter a refractory period and cannot be activated again * Potassium channels permit an outward potassium current, repolarising the cell

Answer 34

Because the current generated locally by depolarization changes the transmembrane potential in adjacent areas of membrane, also depolarizing it

Answer 35

* **Myelination** - myelinated fibres conduct faster * **Thickness of the fibre** - thicker fibres conduct faster * **Properties of the membrane** - the lower the capacitance and resistance the faster the conduction * **Properties of the extra-axonal environment** e.g. electrolyte derangement (hyponatraemia, hypermagneseamia, acidosis and hypothermia all decrease the velocity of nerve conduction

Answer 36

It describes the post-spike negative dip in transmembrane potential, which transiently falls below the normal resting membrane potential. It happens because of persistent calcium-activated potassium channel activity, which are opened by the intracellular influx of calcium during the action potential

Answer 37

The ability of the membrane to store charge; the greater the capacitance the more charge needs to be displaced by the local circuit and therefore the greater the current required in that local circuit. In short, for faster conduction, you want a low-capacitance membrane that carries barely any charge

Answer 38

The resistance to ion flow along the axon, measured between two flat cut ends of the axon. Ion flow requires substrate to flow through, and therefore more axoplasm usually means better conduction

Answer 39

* Most of an axon is covered in myelin sheath, not much action potential propagation happens over the myelinated length * The sodium channels are concentrated at the unmyelinated regions between myelin segments (nodes of Ranvier) * The action potential can propagate from one node to another

Answer 40

The phenomenon where the action potential of one neuron, through an intermediate signal molecule, facilitates a change in the state of another neuron, to which it is connected by a synapse.

Answer 41

A narrow (20-30nm) junction between two neurons

Answer 42

They are molecules used for synaptic signalling. Some shared properties are: * released from a presynaptic terminal in response to calcium-dependent depolarisation * received by specific receptors on the postsynaptic neuron * subsequently reabsorbed into the presynaptic neuron or glia, or metabolised into an inactive form by enzymes to terminate the stimulation * a single neurotransmitter tends to be dominant in any given neuron (Dale's principle), although this is not always true

Answer 43

Glutamate Dopamine Noradrenaline Acetylcholine (nicotinic receptors)

Answer 44

GABA Serotonin Acetylcholine (muscarinic receptors)

Answer 45

* A nerve impulse is conducted to the presynaptic endplate of the neuron * At the endplate, the neurotransmitter substance is stored in vesicles * The arrival of an action potential and the depolarisation of the presynaptic membrane causes the release of the neurotransmitters into the synaptic cleft * The release is generally mediated by intracellular calcium entry acting as a secondary messenger * The released neurotransmitters cross the cleft and bind to their receptors * The either alters the threshold potential or directly produces depolarisation

Answer 46

They are broadly referred to as the SNARE family * synaptotagmin * synaptobrevin * syntaxin They are responsible for mediating the fusion of vesicles with the presynaptic membrane, and the exocytosis of vesicle contents

Answer 47

* Bind to the post-synaptic receptors, producing some change in the other neuron * Bind to the pre-synaptic receptors on the same neuron which had just released it, and therefore exerting some soft of feedback effect

Answer 48

Usually, by the action of various reuptake pumps or more rarely by the activity of a high-affinity enzyme that destroys the neuotransmitted molecule, like acetylcholinesterase

Answer 49

**Skeletal and cardiac muscle** calcium-induced conformational change of tropomyosin and troponin, leading to exposure of actin sites **Smooth muscle** calcium induces calmodulin to activate MLCK, which phosphorylates myosin light chains

Answer 50

**Skeletal and cardiac muscle** calcium dissociation away from tropomyosin and troponin **Smooth muscle** dephosphorylation of myosin light chains by myosin light chain phosphatase

Answer 51

**Skeletal muscle** minor **Smooth muscle** central **Cardiac muscle** regulatory

Answer 52

A specially organised organelle that mainly plays the role in coordinating calcium traffic

Answer 53

It consists of a large anterior horn cell, its motor axon, and the skeletal muscle fibres innervated by that axon

Answer 54

* Intracellular calcium binds to calmodulin (there is no troponin) * Calmodulin activates myosin light chain kinase * Myosin light chain kinase phosphrylates the head of myosin * Only phosphorylated myosin heads can participate in cross-bridge cycling * Contraction then occurs via actin-myosin bridge formation

Answer 55

* When calcium concentration decreases, myosin light chain phosphatase dephosphorylates the myosin light chain kinase and puts an end to the contraction * Myosin light chain phosphatase is activated by cGMP-dependent protein kinase, and is therefore responsive to nitric oxide

Answer 56

A sense organ, an afferent neuron, one of more synapses of a central integrating system, an efferent neuron and an effector

Answer 57

The afferent neurons enter via the dorsal roots or cranial nerves and have their cell bodies in the dorsal root ganglia or in the homologous ganglia of the cranial nerves. The efferent fibres leave via the ventral route or corresponding motor cranial nerves.

Answer 58

* The sense organ generates a **receptor potential** whose magnitude is proportional to the strength of the stimulus * The afferent nerve generates an **all or nothing** action potential, the number being proportional to the receptor potential * In the CNS, the responses are graded in terms of **excitatory post-synpaptic potentials (EPSPs)** and **inhibitory post-synaptic potentials (IPSPs)** at synaptic juntions * The efferent nerve is **all or nothing** potential

Answer 59

The stimulus that triggers a reflex. It is often very precise

Answer 60

alpha motor neurons

Answer 61

All neural influences affecting muscular contraction ultimately funnel through the alpha motor neurons to the muscles, and they are therefore called the final common pathway.

Answer 62

The simplest reflex arc is one with a single synapse between the afferent and efferent neurons, these are called **monosynaptic** reflexes. Reflex arcs in which there interneurons are interposed between the afferent and efferent neurons are called **polysynaptic** reflexes

Answer 63

When a skeletal muscle with an intact nerve supply is stretched, it contracts. This response is called the stretch reflex.

Answer 64

* Stimulus - stretch of the muscle * Response - contraction of the muscle * Sense organ - a small encapsulated spinkle-like structure called the muscle spindle * Neurotransmitter - glutamate * Example - knee jerk reflex

Answer 65

1. A group of specialised **intrafusal muscle fibres** with contractile polar ends and a non-contractile centre 2. Large diameter myelinated **afferent nerves** originating in the central portion of the intrafusal fibres 3. Small diameter myelinated **efferent nerves** supplying the polar contractile regions of the intrafusal fibres

Answer 66

Changes in muscle length are associated with changes in joint angle; thus muscle spindles provide information on position - proprioception

Answer 67

The intrafusal muscles fibres are found parallel to the extrafusal muscle fibres (the regular contractile units of the muscle) with the ends of the spindle capsule attached to the tendons at each end of the muscle

Answer 68

* **Nuclear bag fibre** contains many nuclei in a dilated central area. There are two types *dynamic* and *static* * **Nuclear chain fibre** is thinner and shorter and lacks a definite bag. | Typically a muscle spindle has 2-3 bag fibres and 5 chain fibres

Answer 69

* A single **primary (Ia) ending**, which is very sensitive to the velocity of the change in muscle length during a stretch *(dynamic response)* * Up to 8 **secondary (II) endings**, which provide information on the steady state length of the muscle (static response)

Answer 70

Gamma - motor neurons

Answer 71

Ia fibres end directly on motor neurons supplying the extrafusal fibres of the same muscle

Answer 72

**Reaction time** is the time between the application of the stimulus and the response. Knee jerk - 19-24ms **Central delay** is the time taken for the reflex activity to traverse the spinal cord. Knee jerk is 0.6-0.9ms

Answer 73

They stop firing when the muscle is made to contract by electrical stimulation of the alpha motor neurons to the extrafusal fibres because the muscle shortens when the spindle is unloaded.

Answer 74

Stimulation of the gamma motor neuron does not lead directly to detectable contraction of the muscles because the intrafusal fibers are not strong enough. However, it does stretch the nucleur bag portion of the spindles, deforming the endings and initiating impulses to the Ia fibres. This can in turn lead to reflex contraction of the muscle.

Answer 75

From descending tracts from a number of areas of the brain that also control alpha motor neurons

Answer 76

When a stretch reflex occurs, the muscles that antagonise the muscle involved relax. This is called **reciprocal innervation**

Answer 77

Impulses in the Ia fibres from the muscle spindles on the protagonist muscle cause postsynaptic inhibition of the motor neurons to the antagonists. A collateral from each Ia fibre passes in the spinal cord to an inhibitory interneuron that synapses on a motor neuron supplying the antagonist muscles

Answer 78

Up to a point, the harder a muscle is stretched, the stronger the reflex contraction. However, when the tension becomes great enough, contraction suddenly ceases and the muscle relaxes.

Answer 79

The Golgi tendon organ. The fibres from the Golgi tendon organ make up the Ib group of myelinated, rapidly conducting sensory nerve fibers. Stimulation of these leads to production of IPSPs on the motor neurons from which the fibres arise. The Ib fibres end on the spinal cord on inhibitory interneurons that in turn directly terminate on the motor neurons. They also make excitatory connection with the antagonist muscle motor neurons.

Answer 80

**Muscle tone** - the resistance of a muscle to stretch **Flaccid/Hypotonic** - the muscle offers very little resistance **Hypertonic** - the resistance to stretch is high because of hyperactive stretch reflexes

Answer 81

When the muscles are hypertonic, the sequence of moderate stretch -> muscle contraction, strong stretch -> muscle relaxation. For example, passive flexion of the elbow meets immediate resistance as a result of the stretch receptor in the triceps muscle. Further stretch activates the inverse stretch reflex. The resistance to flexion suddenly stops and the arm flexes. Continued passive flexion stretches the muscle again and the sequence may be repeated

Answer 82

Because of the synaptic delay at each synapse, activity in the branches with fewer synapses reaches the motor neuron first, followed by activity in the longer pathways. This causes prolonged bombardment of the motor neurons from a single stimulus and consequently prolonged responses. Furthermore, some of the branch pathways turn back on themselves, permitting activity to reverberate until it becomes unable to propogated transsynaptic response and dies out. | This is a **reverberating circuit**

Answer 83

A typical polysynaptic reflex that occurs in response to a noxious stimulus to the skin or the subcutaneous tissue or muscles. The response is flexor muscle contraction and inhibition of the extensor muscles, so that the body part stimulated is flexed and withdrawn from the stimulus

Answer 84

When a strong stimulus is applied to a limb, the response includes not only flexion and withdrawal of that limb but also extension of the opposite limb.

Answer 85

The spread of excitatory impulses up and down the spinal cord to more and more motor neurons

Answer 86

They preemt the spinal pathways from any other reflex activity taking place at that moment

Answer 87

A weak stimulus generates one quick flexion movement; a strong stimulus causes prolonged flexion and sometimes a series of flexion movements. This prolonged response is due to prolonged, repeated firing of the motor neurons. This is called **after-discharge**

Answer 88

* The axons of the ganglion cells pass caudally in the optic nerve and **optic tract** to end in the **lateral geniculate body** in the thalamus. * The fibers from each nasal hemiretina decussate in the **optic chiasm**. * In the geniculate body, the fibres from the nasal half of one retina and the temporal half of the other synapse on the cells who axons form the **geniculocalcarine tract**. This tract passes to the occipital lobe of the cerebral cortex.

Answer 89

Some ganglion cell axons bypass the lateral geniculate to project directly to the pretactal area.

Answer 90

The axons of retinal ganglion cells project a detailed spatial representation of the retina on the lateral geniculate body. Each geniculate body has six well-defined layers (layers 1,4,6 from contralateral eye, 2,3,5 from ipsilateral eye). In each layer there is a point for point representation of the retina.

Answer 91

Approx 10-20% from the retina. Major inputs also come from the visual cortex and other brain regions

Answer 92

* **M cells** - large ganglion cells, which add responses from different kinds of cones and are concerned with movement and stereopsis * **P cells** - small ganglion cells, which subtract input of one type of cone from input from another, they are concerned with colour, texture and shape

Answer 93

* The M ganglion cells project to the **magnocellular portion** of the lateral geniculate, whereas the P ganglion cells project to the **parvocellular portion**. * The **magnocellular pathway**, from layers 1 and 2, carries signals for detection of movement, depth and flicker. * The **parvocellular pathway**, from layers 3-6. carries signals for colour vision, texture, shape and fine detail

Answer 94

* **A** - A lesion that interrupts one optic nerve causes blindness in that eye * **B** - Heteronomous (opposite sides of the visual fields) hemianopia - a lesion in the optic chiasm * **C** - Homonomous (same side of the visual fields) hemianopia - a lesion in one optic tract * **D** - Occipital lesions may spare the fibers from the macula because of seperation in the brain of these fibres from the other subserving vision

Answer 95

The cell bodies and fibres of many of the serotonergic, noradrenergic, and cholinergic system. It also contains many of the areas concerned with regulation of heart rate, blood pressure, and respiration. It plays an important role in determining the level of arousal so is called the ascending reticular activation system

Answer 96

A complex polysynaptic pathway arising from the brainstem reticular formation and hypothalamus with projections to the intralaminar and reticular nuclei of the thalamus which, in turn, project diffusely and non-specifically to wide regions of the cortex. Collaterals funnel into it from the long ascending sensory tracts and the trigeminal, auditory, visual and olfactory systems

Answer 97

The complexity of the neuron net and the degree of convergence in it abolish modality specificity, and most reticular neurons are activated with equal facility by different sensory stimuli. Therefore the system is non-specific

Answer 98

Unmyelinated

Answer 99

**TO** * *Norepinephrine-secreting neurons* with their cell bodies in the hindbrain end in different parts of the hypothalamus * Paraventricular neurons that secrete *oxytocin and vasopressin* project in turn to the hindbrain and the spinal cord * *Epinephrine-secreting neurons* have their cell bodies in the hindbrain and end in the ventral hypothalamus * *Serotonin-secreting neurons* project to the hypothalamus from the raphe nuclei **FROM** * An intrahypothalamic system composed of *dompine-secreting neurons* have their cell bodies in the arcuate nucleus and end on or near the capillaries in the median eminence.

Answer 100

* **Temperature regulation** * **Neuroendocrine regulation** * Catecholamines * Vasopressin * Oxytocin * TSH * ACTH * FSH and LH * Prolactin * **Appetitive behaviour** * Thirst * Hunger * Sexual behaviour * **Defensive reactions** - fear and rage * **Control of body rhythms**

Answer 101

1) Afferents from temperature receptors in the skin, deep tissues, spinal cord, hypothalamus and other parts of the brain 2) Integrating areas include: Anterior hypothalamus responds to heat. Posterior hypothalamus responds to cold

Answer 102

1) Afferents from limbic areas concerned with emotion 2) Integrating areas are dorsal and posterior hypothalamus

Answer 103

1) Afferents from osmoreceptors and 'volume receptors' 2) Integrating areas are supraoptic and paraventricular nuclei

Answer 104

1) Afferents from touch receptors in breast, uterus, genitalia 2) Integrating areas are supraoptic and paraventricular nuclei

Answer 105

1) Afferents from temperature receptors in infants and others 2) Integrating areas include paraventricular nuclei and other neighbouring areas

Answer 106

1) Afferents are from limbic system (emotional stimuli); reticular formation (systemic stimuli); hypothalamic and anterior pituitary cells sensitive to circulating blood cortisol levels; suprachiasmatic nuclei (diurnal rhythm) 2) Integrating areas are paraventricular nuclei

Answer 107

1) Afferents are from hypothalamic cells sensitive to oestrogens, eyes, touch receptors in skin and genitalia of reflex ovulating species 2) Integrating areas are preoptic area and others

Answer 108

1) Afferents from touch receptors in breasts 2) Integrating areas include arcuate nucleus

Answer 109

1) Afferents are from osmoreceptors and angiotensin II uptake 2) Integrating areas include lateral superior hypothalamus and subfornical organ

Answer 110

1) Afferents from glucostat cells sensitive to rate glucose utilisation; leptin receptors 2) Integrating areas are the ventromedial, arcuate and paravertebral nuclai and the lateral hypothalamus

Answer 111

1) Afferents from cells sensitive to circulating oestrogen and androgen 2) Integrating areas from anterior ventral hypothalamus plus in the male, piriform cortex

Answer 112

1) Afferents from sense organs and neocortex 2) Integrating areas are diffuse, in limbic system and hypothalamus

Answer 113

Posterior pituitary

Answer 114

The neural pathways by which sensory information from the peripheral nerves is transmitted to the cerebral cortex.

Answer 115

Fine touch, vibration and proprioception In the spinal cord it travels in the dorsal column, in the brainstem it is transmitted through the medial lemniscus

Answer 116

1. **First order neurons** - carry sensory information regarding touch, vibration and proprioception from the peripheral nerves to the medulla oblongata 2. **Second order neurons** begin in the cuneate nucleus or gracilis - they **decussate** in the medulla oblongata and travel in the contralateral medial lemniscus to reach the thalamus 3. **Third order neurons** transmit the signals from the thalamus to the ipsilateral primary sensory cortex

Answer 117

* **Signals from the upper limb (T6 and above)** - travel in the fasciculus cuneatus (lateral part of the dorsal column) - they then synapse in the nucleus cuneatus * **Signals from the lower limb (T6 and below)** - travel in the fascilulus gracilis (medial part of the dorsal column) - they then synapse in the nucleus gracilis

Answer 118

* **Anterior spinothalamic tract** - crude touch and pressure * **Lateral spinothalamtic tract** - pain and temperature

Answer 119

* **First order neurons** arise from sensory receptors in the periphery, enter the spinal cord, ascend 1-2 vertebral levels, and synapse at the tip of the dorsal horn (the substantia gelatinosa) * **Second order neurons** then **decussate** within the spinal cord and split to travel to the thalamus in two different pathways - the anterior and lateral spinothalamic tracts * **Third order neurons** carry the signals from the ventral posterolateral nucleus in the thalamus to the ipsilateral primary sensory cortex of the brain

Answer 120

The tracts that carry unconscious proprioceptive.

Answer 121

Loss of proprioception and fine touch on the ipsilateral side as it decussates in the medulla

Answer 122

A hemisection of the spinal cord DSML pathway - loss of ipsilateral proprioception and find touch Anterolateral system - contralateral loss of pain and temperature sensation It will also involve the motor tracts, causing a ipsilateral hemiparesis

Answer 123

* **Pyramidal** tracts originate in the cerebral cortex, carrying motor fibres to the spinal cord and brainstem. They are resposible for the voluntary control of the musculature of the body and the face * **Extra-pyramidal** tracts originate in the brainstem, carrying motor fibres to the spinal cord. They are responsible for the involuntary and autonomic control of all musculature, such as muscle tone, balance, posture and locomotion

Answer 124

There are no synapses within the descending pathways. At the termination of the descending tracts, the neurons synapse with a lower motor neurone. Thus, all the neurons within the descending tract are called as upper motor neurons. Their cell bodies are found within the cerebral cortex of the brain stem, with their axons remaining in the CNS

Answer 125

* **Corticospinal tract** - supplies the musculature of the body * **Corticobulbar tract** - supplies the musculature of the head and neck

Answer 126

It begins in the cerebral cortex, receiving input from the primary motor cortex, the premotor cortex and the supplementary motor area. After originating from the cortex, the neurons converge, and descend through the internal capsule, the crus cerebri of the midbrain, the pons and into the medulla

Answer 127

* The **lateral corticospinal tract** decussates in the medulla, then descends into the spinal cord, terminating at the ventral horn. From the **ventral horn**, the lower motor neurons go on to supply the muscles of the body * The **medial corticospinal tract** remains ipsilateral, descending into the spinal cord. They then decussate and terminate in the ventral horn of the cervical and upper thoracic segmental levels

Answer 128

The corticobulbar tracts arise from the lateral aspect of the primary motor cortex. They receive the same inputs as the corticospinal tracts. The fibres converge and pass through the internal capsule to the brainstem. The neurons terminate on the motor nuclei of the cranial nerves. Here, they synapse with lower motor neurons, which carry the signals to the muscles of the face and neck.

Answer 129

**Bilaterally** *Except* for upper motor neurons for the **facial nerve (CN VII)** have contralateral innervation below the eyes and the upper motor neurons for the **hypoglossal nerve (CN XII)** only provide contralateral innervation

Answer 130

They originate in the brainstem, carrying motor fibres to the spinal cord. They are responsible for involuntary and autonomic control of all musculature, such as muscle tone, balance, posture and locomotion. The four tracts are: vestibulospinal, reticulospinal, rubrospinal and tectospinal

Answer 131

The vestibulospinal and reticulospinal tracts do **not** decussate, providing ipsilateral innervation. The rubrospinal and tectospinal tracts **decussate**, therefore provide contralateral innervation.

Answer 132

There are two vestibulospinal tracts; medial and lateral. They arise from the vestibular nuclei, which receive input from the organs of balance. The tracts convey this balance information to the spinal cord, where it remains ipsilateral. Fibres in this pathway control balance and posture by innervating the 'anti-gravity' muscles (flexors of the arms, extensors of the legs) via the lower motor neurons

Answer 133

There are two: * The **medial reticulospinal tract** arises from the *pons*. It *facilitates* voluntary movements and *increases* muscle tone * The **lateral reticulospinal tract** arises from the *medulla*. It *inhibits* voluntary movements, and *reduces* muscle tone

Answer 134

The rubrospinal tract originates from the red nucleus, a midbrain structure. As the fibres emerge, they decussate and descend into the spinal cord. Thus, they have **contralateral** innervation. It's exact function is unclear, but it is thought to play a role in fine hand movements

Answer 135

The tectospinal tract begins at the superior collilculus of the midbrain. The superior collilculus receives input from the optic nerves. The neurons then quickly decussate and enter the spinal cord. They terminate at the cervical levels of the spinal cord. It coordinates movements of the head in relation to visual stimuli

Answer 136

Symptoms would occur on the **contralateral** side of the body. Symptoms include hypertonia, hyperreflexia, clonus, Babinski's sign, muscle weakness The anterior corticospinal tract remains ipsilateral, descending into the spinal cord. They then decussate and terminate in the ventral horn of the cervical and upper thoracic segmental levels

Answer 137

Extension of the hallux in response to blunt stimulation of the sole of the foot

Answer 138

* **Upper motor neuron** - spastic paralysis of the **contralateral** genioglossus. Deviation of the tongue to the contralateral side. * **Lower motor neuron** - deviation of the tongue towards the damaged side

Answer 139

* A lesion in the **upper** motor neuron is forehead sparing * A lesion in the **lower** motor neuron includes the forehead

Answer 140

* The SA node is at the junction of the superior vena cava with the right atria * The AV node is located in the right posterior portion of the interatrial septum.

Answer 141

There are **three**: * Anterior * Middle (tract of Wenckebach) * Posterior (tract of Thorel)

Answer 142

* The Bundle of His gives off a left bundle branch at the top of the interventricular septum, and continues as the right bundle branch. * The left bundle branch divides into an anterior fascicle and a posterior fascicle. * The branches and fascicles run subendocardially down either side of the septum and come into contact with the Purkinje system, whose fibres spread to all parts of the ventricular myocardium.

Answer 143

* Purkinje fibres, specialised conducting cells, are large with fewer mitochondria and striations and distinctly different from a myocyte specialised for contraction. * Compared with Purkinje fibres, cells within the SA node and, to a lesser extent, the AV nodes are smaller and sparsely striated and are less conductive due to their higher internal resistance.

Answer 144

The atrial muscle fibres are separated from those of the ventricles by a fibrous tissue ring, and normally the only conducting tissue between the atria and the ventricles is the Bundle of His.

Answer 145

The SA node develops from the structures on the right side of the embryo and the AV node from structures on the left. This is why in the adult the right vagus is distributed mainly to the SA node and the left vagus mainly to the AV node.

Answer 146

Acetylcholine acts presynaptically to reduce noradrenaline release from the sympathetic nerves and conversely, neuropeptide Y released from neuroadrenergic endings may inhibit the release of acetylcholine.

Answer 147

The individual fibres are separated by membranes, but depolarisation spreads rapidly through them as if they were syncytium because of the presence of gap junctions.

Answer 148

* **Phase 0** - the transmembrane action potential of single cardiac muscle cells is characterised by **rapid depolarisation** - *rapid influx sodium* through open sodium channels * **Phase 1** - an initial rapid **repolarisation** - inactivation of sodium channels * **Phase 2** - a **plateau** phase - slow *influx of calcium* through slower opening calcium channels * **Phase 3** - a **slow repolarisation** phase - slow *potassium efflux* * **Phase 4** - return to the resting membrane potential

Answer 149

Rhythmically discharging cells have a membrane potential that after each impulse, declines to the firing level. Thus, this **pre-potential** triggers the next impulse.

Answer 150

* At the peak of each impulse, **I*k* begins** and brings about **repolarisation**. * **I*k* then declines**, and a channel permeable to both sodium and potassium is activated. Because this channel is activated following hyperpolarisation, it is referred to as an **'h' channel.** * As **I*h* increases**, the membrane begins to **depolarise**, forming the first part of the **pre-potential**. * **Calcium channels then open** - the action potentials in the SA and AV node are largely due to calcium, with no contribution of sodium influx.

Answer 151

There are two types of calcium channels in the heart. * **T (transient)** channels - the calcium current (I*Ca*) due to opening of the T channels completes the prepotential. * **L (long-lasting)** channels - the calcium current (I*Ca*) due to opening of the L channels produces the impulse

Answer 152

There is **no sharp, rapid, depolarising spike** before the plataeu, as there is in other parts of the conducting system and in the atrial and ventricular fibres. In addition, pre-potentials are normally prominent only in the SA or AV nodes, unless the muscle fibres are abnormal or damaged.

Answer 153

* The membrane becomes **hyperpolarised** and the slope of the prepotentials is decreased because the **acetylcholine released** at the nerve endings **increases the K+ conductance** of the nodal tissues. * This action is mediated by **M2 muscarinic receptors**, which, via the βγ subunit of a G protein, open a special set of K+ channels. The resulting I*KAch* slows the depolarising effect if I*h*. * In addition, activation of the M2 receptors **decreases cAMP** in the cells, and this *slows* the opening of **Ca2+ channels.** * The result is a **decrease in firing rate**.

Answer 154

* It speeds the depolarising effect of I*h*, and the **rate of spontaneous dicharge increases**. * **Noradrenaline** secreted by the sympathetic endings binds to the **β1 receptors** and the resulting **increase** in intracellular **cAMP** facilitates the **opening of the L channels**, increasing I*Ca* and the rapidity of the depolarisation phase of the impulse

Answer 155

* Depolarisation initiated in the SA node spreads radially through the atria, then converges on the AV node. * From the top of the septum, the wave of depolarisation spreads rapidly in the conducting Purkinje fibres to all parts of the ventricles. * Depolarisation of the the ventricular muscle **starts at the left side of the interventricular septum** and moves to the right across the mid-portion of the septum * It then spreads down the septum to the apex of the heart and **returns along the ventricular walls to the AV groove**, proceeding from the endocardial to epicardial surface * The last parts of the heart to be depolarised are the posterobasal portion of the left ventricle, the pulmonary conus, and the uppermost part of the septum.

Answer 156

0.1 seconds

Answer 157

0.08 - 0.1 seconds

Answer 158

The ECG may be recorded by using an **active** or **exploring** electrode connected to an indifferent electrode at zero potential (**unipolar recording**) or by using two active electrodes (**bilpolar recording**).

Answer 159

In a volume conductor, the sum of the potentials at the points of an equilateral triangle with a current source in the centre is zero at all times. A triangle (**Einthoven's)**, with the heart at the centre can be approximated by placing electrodes on both arms and the left leg. **These are the three standard leads of an ECG.**

Answer 160

Depolarisation moving toward an active electrode in a volume conductor produces a positive deflection, whereas depolarisation moving in the opposite direction produces a negative deflection.

Answer 161

* **P wave** - atrial depolarisation * **QRS complex** - ventricular depolarisation * **T wave** - ventricular repolarisation * **U wave** - an inconsistent finding that may be due to ventricular myocytes with long action potentials

Answer 162

The **standard limb leads** each measure the differences in potential between two limbs. * In **Lead I**, the electrodes are connected so that an upward deflection is inscribed when the left arm becomes positive relative to the right (left arm positive). * In **Lead II**, the electrodes are on the right arm and the left leg, with the leg postivity. * In **Lead III**, the electrodes are on the left arm and left leg with the leg positive

Answer 163

* **PR interval** - 0.12-0.20 - AV conduction * **QRS duration** - 0.08 - 0.10 - Ventricular depolarisation * **QT interval** - 0.40 - 0.43 - Ventricular action potential * **ST interval** - 0.32 - plateau portion of the ventricular action potential

Answer 164

Leads that record the potential difference between an **exploring electrode** and an **indifferent electrode**. * There are six unipolar chest leads V1-V6 and three unipolar limb leads: VR (right arm), VL (left arm) and VF (left foot) * **Augmented limb leads** put a before the above things, aVR, aVL and aVF. They are recording between the one, augmented limb and the other two limbs.

Answer 165

They can be placed at the tips of catheters and inserted into the oesophagus or the heart

Answer 166

**aVR** looks at the cavities of the ventricles and all waves should have negative deflections because all the pathways lead away from it

Answer 167

**aVL and aVF** look at the ventricles and the deflections are either positive or biphasic because the pathways lead towards them

Answer 168

* **V1 and V2** should not have a Q wave and only has a small positive inflection at the start of the QRS, because ventricular depolarisation moves across the septum from left to right toward the exploring electrode. * The wave of excitation then moves down the septum and into the left ventricle away from the electrode, producing a large S wave. * Finally, it moves back along the ventricular wall toward the electrode, producing the return to the isoelectric line.

Answer 169

In the left ventricular leads, there may be a small Q wave (left to right septal depolarisation) and there is a large R wave (septal and left ventricular depolarisation) followed in V4 and V5 by a moderate S wave (late depolarisation of the ventricular walls moving back towards the AV junction)

Answer 170

Because the standard limb leads are records of the potential differences between two points, the deflection in each lead at any instant indicates the magnitude and direction of the electromotive forces generated in the heart in the axis of the lead. This is the **cardiac axis**.

Answer 171

If it is assumed that the heart lies in the centre of the triangle, an **approximate mean QRS vector** is often plotted by using the average QRS deflection in each lead. They can be approximated by measuring the net differences between the positive and negative peaks of the QRS.

Answer 172

-30 to +110 degrees is normal. Left or right axis deviation is said to be present if the axis falls to the left of -30 or to the right of +110

Answer 173

During inspiration, impulses in the vagi from the stretch receptors in the lungs inhibit the cardio-inhibitory area in the medulla oblongata. The tonic vagal discharge that keeps the heart rate slow decreases and the heart rate rises.

Answer 174

When conduction from the atria to the ventricles is completely interrupted and the ventricles beat at a slow rate and independently of the atria. The block may be in the AV node (**AV nodal block**) or in the conducting system below the node (**infranodal block**)

Answer 175

1. In patients with AV nodal block, the remaining nodal tissue becomes the pacemaker and the rate of the idioventricular rhythm is approx 45 bpm. 2. In patients with infranodal heart block, the ventricular pacemaker is located more peripherally in the conduction system and the ventricular rate is slower, approx 30 bpm but can go down to 15bpm. The resultant cerebral ischaemia causes dizziness and fainting (**Stokes-Adams syndrome**)

Answer 176

* **First-degree heart block** is where all the atrial impulses reach the ventricles but the PR interval is abnormally long. * **Second-degree heart block** is where not all the atrial impulses are conducted to the ventricles. * **Mobitz type 1** is where a ventricular beat may follow every second or third atrial beat (2:1 or 3:1 block) * **Mobitz type 2 - Wenckebach** is where there are repeated sequences of beats in which the PR interval lengthens progressively until a ventricular beat is dropped.

Answer 177

Excitation passes normally down the bundle on the intact side and then sweeps back through the muscle to activate the ventricle on the blocked side. The ventricular rate is therefore normal but the QRS wave looked deformed and prolonged

Answer 178

* Block can occur in the anterior or posterior fascicle of the left bundle branch, producing a **hemiblock/fascicular block**. * Left anterior hemiblock produces abnormal left axis deviation in the ECG, whereas left posterior hemiblock produces abnormal right axis deviation. * It is not uncommon to find combinations of fascicular and branch blocks - **bifascicular and trifascicular blocks**

Answer 179

Normally, myocardial cells do not discharge spontaneously, and the possibilty of spontaneous discharge of the His bundle and Purkinje fibres is low because the pacemaker discharge of the SA node is more rapid than their rate of spontaneous discharge. However, in abnormal conditions, the His-Purkinje fibres or the myocardial fibres may discharge spontaneously. In these conditions, **increased automaticity** is said to be present.

Answer 180

If it discharges once, the result is a beat that occurs before the expected next normal beat and transiently disrupts the cardiac rhythm (atrial, nodal or ventricular **extrasystole or premature beat**) If the focus discharges more than repetitively at a rate higher than the that of the SA node, it produces rapid, regular tachycardia (atrial, ventricular, or nodal **paroxysmal tachycardia** or **atrial flutter**)

Answer 181

A defect in conduction that permits a wave of excitation to propagate continuously within a closed circuit. If the re-entry is in the AV node, the re-entrant activity depolarises the atrium, and the resulting atrial beat is called an **echo beat**. In addition, the re-entrant activity propogates down to the ventricle, producing paroxysmal nodal tachycardia

Answer 182

250-300/min In the most common form, there is a large counterclockwise circus movement in the right atrium. It is normally associated with at least 2:1 block because the ventricles can't beat that fast.

Answer 183

In paroxysmal atrial tachycardia and flutter, the ventricular rate may be so high that diastole is too short for adequate filling of ventricles with blood between contractions. Consequently, cardiac output is reduced and symptoms of heart failure occur.

Answer 184

* Premature beats that originate in an ectopic ventricular focus usually have **bizarre shaped prolonged QRS complexes** because of the slow spread of the impulse from the focus through the ventricular muscle to the rest of the ventricle. * They are usually incapable of exciting the bundle of His, and retrograde conduction to the atria therefore does not occur. Meanwhile, the next succeeding normal SA node impulse depolarises the atria. Therefore, the **P wave is usually buried in the QRS.** * If the normal impulse reaches the ventricles, they are still in the refractory period. * However, the second succeeding impulse from the SA node produces a normal beat. Thus, ventricular premature beats are followed by a **compensatory pause** that is often longer than the pause after an atrial ectopic.

Answer 185

A form of ventricular tachycardia where the QRS morphology varies

Answer 186

The ventricular muscles contract in a totally irregular and ineffective way because of the very rapid discharge of multiple ventricular ectopic foci or a circus movement.

Answer 187

The vulnerable period coincides in time with the midportion of the T wave; that is, it occurs at a time when some of the ventricular myocardium is depolarised, some is incompletely repolarised and some is completely repolarised.

Answer 188

An indication of vulnerability of the heart during repolarisation is the fact that in patients in whom the QT interval is prolonged, cardiac repolarisation is irregular and the incidence of ventricular arrhythmias and sudden death increases.

Answer 189

It can be caused by different drugs, electrolyte abnormalities, and myocardial ischaemia. It can also be genetic, often causing reduced function of the potassium channels by alterations in their structure

Answer 190

It is accelerated AV conduction. Normally, the only conducting pathway between the atria and the ventricles in the AV node. Individuals with WPW syndrome have an additional aberrant muscular or nodal tissue connection (**bundle of Kent**) between the atria and ventricles. This conducts quicker than the slowly conducting AV node, and one ventricle is excited early.

Answer 191

The manifestations of the Bundle of Kent activation merge with the normal QRS pattern, producing a short PR interval and a prolonged QRS deflection slurred on the upstroke, with a normal interval between the start of the P wave and the end of the QRS complex.

Answer 192

They often follow an atrial premature beat. This beat conducts normally down the AV node but spreads to the ventricular end of the aberrant bundle, and the impulse is transmitted retrograde to the atrium, forming a circus movement

Answer 193

There is a mutation in a gene that codes for AMP-activated protein kinase

Answer 194

Individuals with short PR intervals and normal QRS complexes. In this condition, depolarisation presumably passes from the atria to the ventricles via an aberrant bundle that bypasses the AV node but enters the intraventricular conducting system distal to the node.

Answer 195

1. Atrial systole 2. Isovolumetric ventricular contraction 3. Ventricular ejection 4. Isovolumetric ventricular relaxation 5. Ventricular filling

Answer 196

The mitral and tricuspid valves are open and the aortic and pulmonary valves are closed. Blood flows into the heart throughout diastole, filling the atria and ventricles. The rate of the filling decreases as the ventricles become distended and, especially when the heart rate is low, the cusps of the AV valve drift toward the closed position. **The pressure in the ventricles remains low**.

Answer 197

Around 70%

Answer 198

* Contraction of the atria propels some additional blood into the ventricles * Contraction of the atrial muscle narrows the orifices of the superior and inferior vena cava and pulmonary veins, and the inertia of the blood moving towards the heart tends to keep blood in it. However, despite these inhibitory influences, there is some regurgitation of blood into the veins.

Answer 199

* The AV valves close. * Ventricular muscle initially shortens relatively little, but intra-ventricular pressure rises sharply as the myocardium presses on the blood in the ventricle. * During isovolumetric contraction, the AV valves bulge into the atria, causing a small but sharp rise in atrial pressure. * The end of isovolumetric ventricular contracion is when he pressure in the ventricles excees the pressure in the aorta and pulmonary artery and the aortic and pulmonary valves open.

Answer 200

* Ejection is rapid at first, slowing down as systole progresses. * The intraventricular pressure rises to a maximum and then declines somewhat before ventricular systole ends. * Late in systole, pressure in the aorta actually exceeds that in the left ventricle, but for a short period momentum keeps the blood flowing forward. * The AV valves are pulled down by the contractions of the ventricular muscle, and atrial pressure drops.

Answer 201

0.05 seconds

Answer 202

**Aorta** - 80mmHg, 10.6kPa **Pulmonary artery** - 10mmHg **Left ventricle** - 120mmHg **Right ventricle** - 25mmHg

Answer 203

**Volume of blood ejected** - 70-90mL **End-diastolic ventricular volume** - 130mL **End-systolic ventricular volume** - 50ml

Answer 204

The percentage of the end-diastolic ventricular volume that is ejected with each stroke, approx 65%

Answer 205

* Once the ventricular muscle is fully contracted, the already falling ventricular pressures drop more rapidly. * It lasts for about 0.04 seconds * It ends when the momentum of the ejected blood is overcome and the aortic and pulmonary valves close, setting up transient vibrations in the blood and blood vessel walls.

Answer 206

After the aortic and pulmonary valves close, pressure continues to drop rapidly during the period of isovolumetric volumetric relaxation. Isovolumetric relaxation ends when the ventricular pressure falls below the atrial pressure and the AV valves open, permitting the ventricles to fill.

Answer 207

Although events on two sides of the heart are similar, they are somewhat asynchronous. Right atrial systole precedes left atrial systole, and contraction of the right ventricle starts after that of the left. However, since the pulmonary artery pressure is lower than aortic pressure, right ventricular ejection begins before that of the left.

Answer 208

During expiration, the pulmonary and aortic valves close at the same time; but during inspiration, the aortic valve closes slightly before the pulmonary valve. The slower closure of the pulmonary valve is due to lower impedence of the pulmonary vascular tree.

Answer 209

The duration of systole can decrease from 0.27 seconds at 65bpm to 0.16 seconds at 200 bpm. However, the duration of systole is much more fixed than diastole, and when the heart rate is increased, diastole is shortened to a much greater degree. The duration of diastole can decrease from 0.62 seconds and 65bpm to 0.14 seconds at 200bpm

Answer 210

It is during diastole that coronary blood flow to the subendocardial portions of the left ventricle occurs and this is when most of the ventricular filling occurs.

Answer 211

It is the period from the onset of the QRS complex to the closure of the aortic valves, as determined by the second heart sound.

Answer 212

The period from the beginning of the carotid pressure rise to the **dicrotic notch** (a small oscillation of the falling phase of the pulse wave caused by vibrations set up when the aortic valve snaps shut, is visible if the pressure wave is recorded but is not palpable at the rest.)

Answer 213

PEP is the difference between QS2 and LVET and represents the time for the electrical as well as the mechanical events that precede systolic ejection.

Answer 214

* **Aorta** - 4m/s * **Large arteries** - 8m/s * **Small arteries** - 16m/s

Answer 215

When the aortic valve is incompetent (aortic regurgitation), the pulse is particularly strong, and the force of systolic ejection may be sufficient to make the head nod with each heartbeat.

Answer 216

* During diastole, the ventricle fills and pressure increases from d to a * Pressure then rises sharply from a to b during isovolumetric contraction and from b to c during ventricular ejection * At c, the aortic valves close and pressure falls during isovolumetric relaxation from c back to d.

Answer 217

* The **a wave** is due to atrial systole - some blood regurgitates back into the great veins and the resultant rise in JVP contributes to the a wave * The **c wave** is the transmitted manifestation of the rise in atrial pressure produced by the bulging of the tricuspid valve into the atria during isovolumetric contraction * The **v wave** mirrors the rise in atrial pressure before the tricuspid valve opens during diastole

Answer 218

Venous pressure falls during inspiration as a result of the increased negative intrathoracic pressure and rises again during expiration.

Answer 219

* The **first sound** is caused by vibrations set up by the sudden closure of the AV valves at the start of ventricular systole * The **second sound** is caused by vibrations associated with the closure of the aortic and pulmonary valves just after the end of ventricular systole. * The **third sound** coincides with the period of rapid ventricular filling and is probably due to vibrations set up by the inrush of the blood - occurs in about 1/3 of young people through diastole. * A **fourth sound** can sometimes be heard immediately before the first sound when atrial pressure is high or the ventricle is stiff in conditions such as ventricular hypertrophy. It is due to ventricular fillings and is largely pathological.

Answer 220

* **First sound** - duration 0.15 seconds, 25-45Hz - it is soft in bradycardia * **Second sound** - duration 0.12 seconds, 50Hz - it is loud and sharp when the diastolic pressure in the aorta or pulmonary artery is elevated * **Third sound** - when present duration 0.1 seconds

Answer 221

Systolic murmurs occur in aortic stenosis and pulmonary regurgitation

Answer 222

During diastole

Answer 223

Flow = Pressure/Resistance Therefore, flow in any portion of the vascular system is therefore equal to the effective perfusion pressure/resistance.

Answer 224

The mean intraluminal pressure at the arterial end minus the mean pressure at the venous end

Answer 225

Pressure/flow = dyne.s/cm^5. To avoid dealing with such complex units, resistance in the CVS is sometimes expressed in R unit, which are obtained by dividing pressure in mmHg by flow in mL/s For exampled, when the mean aortic pressure is 90mmHg and the left ventricular output is 90mL/s, the total peripheral resistance is 1 R unit.

Answer 226

Usually with Doppler flow meters

Answer 227

The flow of blood in straight blood vessels, is normally laminar. Within the blood vessels, an infinitely thin layer of blood in contact with the wall of the vessel does not move. The next layer within the vessel has a low velocity, the next a higher velocity and so forth, velocity being greatest in the centre of the stream. Laminar flow occurs at velocities up to a certain critical velocity. At or above this velocity, blood flow is turbulent

Answer 228

The probability of turbulent blood flow is related to velocity of blood flow but also the diameter of the vessel and the viscosity of the blood. This probability can be expressed by the ratio of inertial to viscous forces as follows: Re = pDV/n. p is the Density of the fluid; D is the diameter of the tube; V is the velocity of the flow and n is the viscosity of the fluid

Answer 229

Flow is usually not turbulent if Re is less than 2000. When Re is more than 3000, turbulence is almost always present

Answer 230

**Velocity** is displacement per unit time **Flow** is volume per unit time Velocity (V) is proportional to flow (Q) divided by the area of the conduit (A). Therefore Q = A x V so if flow stays constant then velocity increases in direct proportion to any decrease in A. The average velocity of fluid movement at any point in a system of tubes in parallel is inversely proportional to the **total** cross-sectional area at that point.

Answer 231

The relationship between the flow in a long narrow tube, the viscosity of the fluid and the radius of the tube is expressed mathematically in the **Poiseuille-Hagen formula**:

Answer 232

Flow varies directly with the fourth power of the radius. Flow through a vessel is doubled by an increase of only 19% in it's radius

Answer 233

Resistance is inversely proportional with the fourth power of the radius. When the radius is doubled, resistance is reduced to 6% of its previous value

Answer 234

Plasma is about 1.8 times as viscous as water, whereas whole blood is 3-4 times as viscous as water. Thus, viscosity depends for the most part on the haematocrit

Answer 235

In large vessels, increases in haematocrit causes appreciable increases in viscosity. However, in vessels smaller than 100μm in diameter the viscosity change per unit change in haematocrit is muss less than it is in large-bore vessels. This is due to a difference in the nature of flow though the small vessels, known as the Fahraeus-Lindqvist effect.

Answer 236

In small vessels, erythrocytes move to the center of the vessel, leaving cell-free plasma at the vessel wall. Therefore, the net change in viscosity per unit change in haematocrit is considerably smaller in the body than it is in vitro. This is why haematocrit changes have relatively little effect on the peripheral resistance except when the changes are large.

Answer 237

When the pressure in a small blood vessel is reduced, a point is reached at which no blood flows, even though the pressure is not zero, the intraluminal pressure falls below the pressure exerted by neighbouring tissues. The pressure at which flow ceases if called the critical closing pressure.

Answer 238

The law states than tension in the wall of a cylinder (T) is equal to the product of the transmural pressure (P) and the radius (r) divided by the wall thickness (w)

Answer 239

In a cylinder such as a blood vessel, one radius is infinite to P = T/r. Consequently, the smaller the radius of a blood vessel, the lower the tension in the wall necessary to balance the distending pressure.

Answer 240

**Aneuryms** - the increased radius means at the same pressure there will be a higher tension and more stress therefore a higher risk of perforation **Dilated cardiomyopathy** - the increased radius of the cardiac chamber means a greater tension must be developed in the myocardium to produce any given pressure

Answer 241

A large amount of blood can be added to the venous sytem before the veins become distended to the point where further increments in volume produce a large rise in venous pressure

Answer 242

The capacity of tissues to regulate their own blood flow is referred to as autoregulation

Answer 243

Systemic veins - 50% Heart cavities - 12% Low pressure pulmonary circulation - 18% Aorta - 2% Arteries - 8% Arterioles - 1% Capillaries - 5%

Answer 244

The intrinsic contractile response of smooth muscle to stretch. As the pressure rises, the blood vessels are distended and the vascular smooth muscle fibers that surround the vessels contract. Possibly, the muscle could response to the tension in the vessel wall, so as the pressure increased, the radius would need to decrease in order to keep the same tension

Answer 245

Vasodilator substances tend to accumulate in active tissues, and these 'metabolites' also contribute to autoregulation. When blood flow decreases, they accumulate and the vessels dilate; when blood flow increases, they tend to be washed away

Answer 246

In most tissues, decreases in O2 tension and pH. These changes cause relaxation of the arterioles and precapillary sphincters

Answer 247

It can initiate a program of vasodilatory gene expression secondary to production of hypoxia-inducible factor-1α (HIF-1α), a transcription factor with multiple targets

Answer 248

It exerts a direct vasodilator effect, and the temperature rise in active tissues (due to the heat of metabolism) may contribute to vasodilation

Answer 249

It accumulates locally, and has demonstrated dilator activity secondary to the hyperpolarisation of vascular smooth muscle cells.

Answer 250

From argnine in a reaction catalysed by nitric oxide synthase (NOS)

Answer 251

NOS 1 in the nervous system NOS 2 in macrophages and other immune cells NOS 3 found in endothelial cells

Answer 252

NOS 1 and NOS 3 are activated by agents that increase intracellular calcium concentrations, including the vasodilators acetylcholine and bradykinin. NOS 2 is not activated by calcium but is induced by cytokines

Answer 253

**Independently** * Adenosine * ANP * Histamine via H2 receptors **Act on endothelium** * Acetylcholine * Histamine via H1 receptors * Bradykini * Vasoative intestinal peptide (VIP) * Substance P

Answer 254

* When flow to a tissue is suddenly increased by arteriolar dilation, the large arteries to the tissue also dilate. The flow-induced dilation is due to local release of NO. * Products of platelet aggregation also cause release of NO, and the resulting vasodilation helps keep bloods with an intact endothelium patent.

Answer 255

It is a potent vasoconstrictor.

Answer 256

* **Endothelin-1** is found in the brain and kidneys as well as the endothelial cells * **Endothelin-2** is produced primarily in the kidneys and intestine * **Endothelin-3** is present in the blood and is found in high concentrations in the brain. It is also found in the kidneys and GI tract.

Answer 257

Small amounts are secreted into the blood, but for the most part, they are secreted locally and act in a paracrine fashion

Answer 258

The **ET*A*** receptor, which is specific for endothelin-1, is found in many tissues, and mediates the vasoconstriction produced by endothelin-1 The **ET*B*** receptor responds to all three endothelins, and is coupled to Gi. It may mediate vasodilation, and it appears to mediate the developmental effects of the endothelins.

Answer 259

* The **vasodilator** regulators include kinins, VIP, and ANP * Circulating **vasoconstrictor** hormones include vasopressin, noradrenaline, adrenaline and angiotensin II

Answer 260

**Kallidin** can be converted to **bradykinin** by aminopeptidase.

Answer 261

Both peptides are metabolised to forms that are active at the type 1 bradykinin receptor by **kininase 1**, a carboxypeptidase that removed the carboxyl terminal arginine (Arg). In addition, the dipeptidycarboxypeptidase **kininase II** inactivates bradykinin and kallidin by removing from (Phe-Arg) from the carboxyl termal. **Kininase II is the same enzyme as angiotensin-converting enzyme**

Answer 262

* Proteases called kallikreins release the kinins from their precursors - **high-molecular-weight-kininogen** and **low-molecular-weight-kininogen** * *Plasma kallikrien*, circulates in an inactive form that, when activated by active factor XII in the clotting cascade, acts on HMW-kininogen to form bradykinin * *Tissue kallikrien* forms bradykinin from HMW-kininogen and kallidin from LMW-kininogen * HMW-kininogen and activated plasma kallikrien activate factor XII in a positive feedback loop, which is kept in check by the C1-esterase inhibitor (C1INH)

Answer 263

They resemble histamine. * They cause contraction of visceral smooth muscle, but they relax vascular smooth muscle via NO, lowering BP. * They significantly increase vascular permeability resulting in oedema, attract leukocytes, and cause pain upon injection under the skin. * They are formed during active secretion in sweat glands, salivary glands, and the exocrine portion of the pancreas, and they are probably responsible for the increase in blood flow

Answer 264

They are stretch receptors in the walls of the heart and the blood vessels.

Answer 265

The **carotid sinus** and the adventitia of the **aortic arch**

Answer 266

They are located in the walls of the right and left atria at the entrance of the superior and inferior venae cavae and the pulmonary veins, as well as in the pulmonary circulation.

Answer 267

It is a small dilatation of the internal carotid artery just above the bifurcation of the common carotid into external and internal carotid branches

Answer 268

* The afferent nerve fibres from the **carotid sinus** form a distinct branch of the glossopharangeal nerve, the **carotid sinus nerve**. * The afferent nerve fibres from the **aortic arch** form a branch of the vagus nerve, the **aortic depressor nerve**

Answer 269

They are stimulated by distention of the structures in which they are located, and so they discharge at an increased rate when the pressure rises. * Their afferent fibres pass via the glossopharyngeal and vagus nerves to the medulla. * Most of them end in the **nucleus of the tractus solitarius** (NTS). * The excitatory transmitter they secrete is glutamate. * Excitatory (glutamate) projections extend from the NTS to the **caudal ventrolateral medulla** (CVLM), where they stimulate GABA-secreting inhibitory neurons that project to the RVLM. * Excitatory projections also extend from the NTS to the vagal motor neurons in the nucleus anbiguus and dorsal motor nucleus.

Answer 270

* Increased baroreceptor discharge **inhibits** the tonic discharge of **sympathetic** nerves and **excited the vagal innervation** of the heart. * These neural changes produce vasodilation, venodilation, hypotension, bradycardia, and a decrease in cardiac output.

Answer 271

* Baroreceptors are more sensitive to pulsatile pressure than to constant pressure. * A decline in pulse pressure without any change in mean pressure decreases the rate of baroreceptor discharge and provokes a rise in systemic blood pressure and tachycardia.

Answer 272

During systole, a burst of action potentials appear in a single baroreceptor fibre There are few action potentials in early diastole

Answer 273

The overall firing rate is considerably reduced.

Answer 274

The threshold for eliciting activity in the carotid sinus nerve is approx 50mmHg Maximal activity occurs at approximately 200mmHg

Answer 275

In chronic HTN, the baroreceptor reflex mechanism is 'reset' to maintain an elevated rather than a normal blood pressure.

Answer 276

Activation of the reflex allows for rapid adjustments in blood pressure in response to abrupt changes in posture, blood volume, cardiac output, or peripheral resistance during exercise.

Answer 277

A long-term change in blood pressure resulting from loss of baroreceptor reflex control is called neurogenic HTN

Answer 278

* **Type A** - those that discharge primarily during atrial systole * **Type B** - those that discharge primarily in late diastole, at the time of peak atrial filling

Answer 279

It is increased when venous return is increased and decreased by positive-pressure breathing, indicating that these baroreceptors respond primarily to distension of the atrial walls.

Answer 280

Vasodilation and a fall in blood pressure. However, the heart rate is increased rather than decreased

Answer 281

They are activated during ventricular distension. The response is a vagal bradycardia and hypotension, comparable to a baroreceptor reflex. Left ventricular stretch receptors may play a role in the maintenance of vagal tone that keeps the heart rate low at rest.

Answer 282

It is forced expiration against a closed glottis. Valsava maneuvers occur regularly during cough, defecation and heavy lifting.

Answer 283

* The blood pressure rises at the onset of straining because the increase in intrathoracic pressure is added to the pressure of the blood in the aorta. * It then falls because the high intrathoracic pressure compresses the veins, decreasing venous return and cardiac output. * The decreases in arterial pressure and pulse pressure inhibit the baroreceptors, causing tachycardia and a rise in peripheral resistance. * When the glottis is opened and the intrathoracic pressure returns to normal, cardiac output is restored but the peripheral vessels are constricted. * The blood pressure therefore rises above normal, and this stimulates the baroreceptors, causing bradycardia and a drop in pressure to normal levels.

Answer 284

Activation of chemosensitive vagal C fibres in the cardiopulmonary region (juxtacapillary region of alveoli, ventricles, atria, great veins and pulmonary artery) causes profound bradycardia, hypotension and a brief period of apnoea following by rapid shallow breathing

Answer 285

Peripheral arterial chemoreceptors in the **carotid** and **aortic bodies** have very high rates of blood flow. These receptors are primarly activated by a reduction in partial pressure of oxygen (PaO₂), but they also respond to an increase in the partial pressure of carbon dioxide (PaCO₂) and pH.

Answer 286

They exert their main effects on respiration; however, their activation also leads to vasoconstriction. Heart rate changes are variable and depend on various factors, including changes in respiration. A direct effect of chemoreceptor activation is to increase vagal nerve activity.

Answer 287

Hypoxia also produces hyperpnea and increased catecholamine secretion from the adrenal medulla, both of which produce tachycardia and an increase in cardiac output.

Answer 288

It decreases blood flow to the chemoreceptor stimulation due to decreased blood flow to the chemoreceptors and consequent stagnant anoxia of these organs

Answer 289

* **Traube-Hering waves** are fluctuations in BP synchronised with respiration * **Mayer waves** are slow, regular oscillations in arterial pressure that occur at the rate of about one per 20-40 seconds during hypotention. Under these conditions, hypoxia stimulates the **chemoreceptors**.

Answer 290

Moderate hyperventilation, which significantly lowers the CO2 tension of the blood, causes cutaneous and cerebral vasoconstriction in humans, but there is little change in BP

Answer 291

It stimulates the chemoreceptors and baroreceptors, causing a reflex decrease in heart rate. **BUT** The direct peripheral effect of hypercapnia is vasodilation. Therefore, the peripheral and central actions tend to cancel each other out.

Answer 292

There is marked cutaneous and cerebral vasodilation, but vasoconstriction occurs elsewhere and usually there is a slow rise in BP.

Answer 293

An acid protease secreted by the kidney into the bloodstream. The enzyme acts in concert with ACE to form angiotenin II

Answer 294

It is a glycoprotein, made up of two lobules or domains, between which the active site of the enzyme is located in a deep cleft. Two aspartic acid residues are juxtaposed in the cleft and are essential for activity. Thus, renin is an aspartyl protease.

Answer 295

Preprorenin. The **prorenin** that remains after removal of an amino acid sequence has little, if any, biologic activity. After removal of the pro sequence from the amino terminal of prorenin, renin is left.

Answer 296

* Some prorenin is converted to renin in the kidneys, some is secreted. * Prorenin is also secreted by other organs, including the ovaries. * Very little prorenin is converted to renin in the circulation, and active renin is a product primarly, if not exclusively, of the kidneys

Answer 297

80 minutes or less

Answer 298

It is synthesised in the liver with a 32-amino-acid signal sequence that is removed in the endoplasmic reticulum.

Answer 299

Glucocorticoids Thyroid hormones Oestrogens Several cytokines Angiotensin II

Answer 300

* It is a dipeptidyl carboxypeptidase that splits off histidyl-leucine from the physiologically inactive angiotensin I, forming the octapeptide angiotensin II. * It also inactivates bradykinin, with kinins causing the cough associated with ACE-inhibitors

Answer 301

* Most of the ACE in the circulation is located in endothelial cells. * Much of the conversion occurs as the blood passes through the lungs, but conversion also occurs in many other parts of the body.

Answer 302

* A **somatic** form found throughout the body * A **germinal** form found solely in postmeiotic spermatogenic cells and spermatozoe. Somatic ACE has two homogolous extracellular domains, each containing an active side. Germinal ACE has only one extracellular domain and active site.

Answer 303

Angiotensin II is metabolised rapidly; its half-life in the circulation in humans is 1-2 minutes. It is metabolised by various peptidases. It appears to be removed from the circulation by some sort of trapping mechanism in the vascular beds of tissues other than the lungs.

Answer 304

It appears only to function solely as the precursor of angiotensin II and does not have any other established action

Answer 305

* Produces **arteriolar constriction** and a **rise in systolic and diastolic BP** * Acts directly on the adrenal cortex to increase the secretion of **aldosterone**, and the RAA system is a major regulator of aldosterone secretion. * Facilitation of the **release of noradrenaline** by a direct action on postganglionic sympathetic neurons, contraction of mesangial cells with a resulant **decrease in GFR**, and a direct effect on the renal tubules to **increase Na reabsorption** * Acts on the brain to decrease the sensitivity of the baroreflex of the baroreceptor (potentiating the pressor effect). Also **increases water intake** and increases the **secretion of vasopressin** and ACTH

Answer 306

No, it triggers the brain responses by acting on the circumventricular organs, four small structures in the brain that are outside the blood-brain barrier.

Answer 307

* Components of the RAA system are found in the walls of blood vessels and in the uterus, the placenta and the fetal membranes. * Amniotic fluid has a high concentration of prorenin * In addition, at least several components of the RAA system are present in the eyes, exocrine portion of the pancreas, heart, fat, adrenal cortex, testis, ovary, anterior and intermediate lobes of the pituitary, pineal, and brain

Answer 308

* **AT1 receptors** are receptors coupled by a G-protein to phospholipase C, and angiotensin II increases the cytosolic free Ca level. It also activates numerous tyrosine kinases. * **AT2 receptors** act via a G-protein to activate various phosphatases, which is turn antagonise growth effects and open K+ channels. In addition, activation increases the production of NO and therefore cGMP.

Answer 309

As excess of angiotensin II down-regulates the vascular receptors, but it up-regulates the adrenocortical receptors, making the gland more sensitive to the aldosterone-stimulating effect of the peptide.

Answer 310

* The renin in kidney extracts and the bloodstream is produced by the **juxtaglomerular cells**. * These epitheliod cells are located in the media of the afferent arterioles as they enter the glomeruli. * The membrane-lined secretory granules in them have been shown to contain renin. * Renin is also found in agranular **lacis cells** that are located in the junction between the afferent and efferent arterioles

Answer 311

At the point where the afferent arteriole enters the glomerulus and the efferent arteriole leaves it, the tubule of the nephron touches the arterioles of the glomerulus from which it arose. At this location which marks the start of the distal convolution, is called the **macula densa**

Answer 312

The lacis cells, the JG cells and the macula densa consistute the juxtaglomerular apparatus.

Answer 313

**Stimulatory** * increased sympathetic activity via renal nerves * increased circulating catcholamines acting on β1-adrenergic receptors on the juxtaglomerular cells * prostaglandins **Inhibitory** * increased Na+ and Cl- reabsorption across macula densa * increased afferent arteriolar pressure via intra-renal baroreceptors * angiotensin II via the juxtaglomerular cells * vasopressin

Answer 314

Hyponatraemia Diuretics Hypotension Haemorrhage Upright posture Dehydration Cardiac failure Cirrhosis Renal artery constriction Most of these decrease central venous pressure, triggering an increase in sympathetic activity and some also decrease renal arteriolar pressure

Answer 315

* Doppler combined with echo * Direct Fick's method * Indicator dilution method

Answer 316

The amount of a substance taken up by an organ per unit of time is equal to the arterial level of the substance minus the venous level times the blood flow. Arterial O2 content can be measured at any point because it has the same content in all parts of the body. A sample of venous blood in the pulmonary artery is obtained by means of a cardiac catheter

Answer 317

A known amount of a substance such as a dye, or a radioactive isotope is injected into an arm vein and the concentration of the indicator in serial samples of arterial blood is determined. The output of the heart is equal to the amount of indicator injected divided by its average concentration in arterial blood after a single circulation through the heart.

Answer 318

The indicator used is cold saline. The saline is injected into the right atrium through one channel of a double-lumen catheter, and the temperature change in the blood is recorded in the pulmonary artery. The temperature change is inversely proportional to the amount of blood flowing through the pulmonary artery

Answer 319

The amount of blood pumped out of the heart per beat (stroke volume) is about 70mL from each ventricle.

Answer 320

The output of the heart per unit of time (cardiac output) is about 5L/minute

Answer 321

The output per minute per square meter of body surface averages 3.2L

Answer 322

Sleep Moderate changes in environmental temperature

Answer 323

Anxiety and excitement (50-100%) Eating (30%) Exercise (up to 700%) High environmental temperature Pregnancy Adrenaline

Answer 324

Sitting or standing from lying position (20-30%) Rapid arrythmias Heart disease

Answer 325

* The cardiac rate is controlled primarily by the autonomic nerves, with sympathetic stimulation increasing it and parasympathetic stimulation decreasing it. * Stroke volume is also determined in part by neural input, with sympathetic stimuli making the myocardial muscle fibres contract with greater strength and parasympathetic stimuli having the opposite effect, with more and less blood being pumped respectively.

Answer 326

* The cardiac accelerator action of the catecholamines liberated by sympathetic stimulation is referred to as their **chronotropic action** * Their effect on the strength of cardiac contraction is called **inotropic action**

Answer 327

* The initial phase of the contraction is isometric; the elastic component in series with the contractile element is stretched, and tension increases until it is sufficient to lift the load. * The tension at which the load is lifted is the **afterload**. * The muscle then contracts isotonically without developing further tension. * In vivo, the preload is the degree to which the myocardium is stretched before it contracts and the afterload is the resistance against which blood is expelled

Answer 328

When the muscle is stretched, the developed tension increases to a maximum and then declines as stretch becomes more extreme. For the heart, the length of the muscle fibres (extent of the preload) is proportional to the end-diastolic volume.

Answer 329

'The energy of contraction is proportional to the initial length of the cardiac muscle fiber.' The relation between ventricular stroke volume and end-diastolic volume is called the Frank-Starling curve

Answer 330

* When cardiac output is regulated by changes in cardiac muscle fiber length, this is referred to as **heterometric regulation** * Regulation due to changes in contractility independent of length is sometimes called **homometric regulation**

Answer 331

* **An increase in pericardial pressure** as a result of infection or pressure from a tumour * **A decrease in ventricular compliance** ie. an increase in ventricular stiffness produced by MI, infiltrative disease and other abnormalities

Answer 332

* An increase in total blood volume * Constriction of the veins reduces the size of the venous reservoirs, decreasing venous pooling and thus increasing venous return * An increase in the normal negative intrathoracic pressure increases the pressure gradient along which blood flows to the heart * Muscular activity increases it as a result of the pumping action of skeletal muscle

Answer 333

Upwards and to the left

Answer 334

It is known as the **force-frequency relation**. Ventricular extrasystoles condition the myocardium in such a way that the next succeeding contraction is stronger than the preceding normal contraction. This is called the **postextrasystolic potentiation**.

Answer 335

* It is independent of ventricular filling, since it occurs in isolated cardiac muscle and is due to increased availability of intracellular calcium. * A sustained increment in contractility can be produced therapeutically by delivering paired electrical stimuli to the heart in such as way that the second stimulus is delivered shortly after the refractory period of the first

Answer 336

They exert their **inotropic** effect via an action on cardiac β1-adrenergic receptors and Gs, with resultant activation of adenylyl cyclase and increased intracellular cAMP.

Answer 337

They inhibit the breakdown of cAMP and are predictably positively inotropic.

Answer 338

The **positively inotropic** effect of digoxin is due to its inhibitory effect on the Na/K+ATPase in the myocardium, and a subsequent decrease in calcium removal from the cytosol by Na/Ca exchange

Answer 339

Hypercapnia Hypoxia Acidosis Drugs such as procainamide and barbiturates Heart failure

Answer 340

Athletes have lower heart rates, greater end-systolic ventricular volumes and greater stroke volumes at rest. Therefore, they can potentially achieve a given increase in cardiac output by further increases in stroke volume without increasing their heart rate to as a great a degree as an untrained individual.

Answer 341

The basal rate is about 2ml/100g/min and 9ml/100g/min when beating This value is considerably higher than that of resting skeletal muscle

Answer 342

Increases occur during exercise and a number of different states. Cardiac venous O2 tension is low, and little additional O2 can be extracted from the blood in the coronaries so increases in O2 consumption require increases in coronary blood flow.

Answer 343

The intramyocardial tension, the contractile state of the myocardium and the heart rate.

Answer 344

Ventricular work per beat correlates with O2 consumption. The work is the product of stroke volume and mean arterial pressure in the pulmonary artery or the aorta (for the right and left ventricle respectively).

Answer 345

Because aortic pressure is seven times greater than pulmonary artery pressure, the stroke work of the left ventricle is approx seven times the stroke work of the right.

Answer 346

* Pressure work produces a greater increase in O2 consumption than volume work. * In other words, an increase in afterload causes a greater increase in cardiac O2 consumption than does an increase in preload. * This is why angina due to deficient delivery of O2 to the myocardium is more common in AS than in AR. In AS, intraventricular pressure must be increased to force blood through the stenotic valves, whereas in AR, an increase in stroke volume with little change in aortic impedence ocurs.

Answer 347

Two internal carotid arteries and two vertebral arteries.

Answer 348

The basilar artery

Answer 349

The basilar artery and the carotids form the **circle of Willis** below the hypothalamus

Answer 350

Almost exclusively to the cerebral hemisphere on that side. Normally no crossing over occurs, probably because the pressure is equal on both sides.

Answer 351

From the brain by way of the deep veins and dural sinuses empties principally into the internal jugular veins, although a small amount of venous blood drains through the ophthalmic and pterygoid venous plexus, through emissary veins to the scalp, and down the system of paravertebral veins in the spinal canal

Answer 352

**Organ - mL/min - ml/100g/min** * Liver - 1500mL/min - 57.7ml/100g/min * Kidneys - 1260mL/min - 420ml/100g/min * Brain - 750mL/min - 54ml/100g/min * Skin - 462mL/min - 12.8ml/100g/min * Skeletal muscle 840mL/min - 2.7ml/100g/min * Heart muscle 250mL/min - 84ml/100g/min * Whole body - 5400mL/min - 8.6ml/100g/min

Answer 353

* Liver - 27.8% * Kidneys - 23.3% * Brain - 13.9% * Skin - 8.6% * Skeletal muscle - 15.6% * Heart muscle - 4.7%

Answer 354

* Liver - 20.4% * Kidneys - 7.2% * Brain - 18.4% * Skin - 4.8% * Skeletal muscle - 20.0% * Heart muscle - 11.6%

Answer 355

In the choroid plexuses, there are gaps between the endothelial cells of the capillary wall, but the choroid epithelial cells that separate them from the CSF are connected to one another by tight junctions.

Answer 356

The capillaries in the brain resemble nonfenestrated capillaries in muscle, but there are tight junctions between the endothelial cells that limit the passage of sustances via the paracellular route.

Answer 357

The brain capillaries are surrounded by the endfeet of astrocytes. These endfeet are closely applied to the basal lamina of the capillaries, but they do not cover the entire capillary wall, and gaps of about 20nm occur between endfeet. However, the endfeet induce the tight junctions in the capillaries

Answer 358

1) **Postganglionic sympathetic neurons** have their cell bodies in the superior cervical ganglia, and their endings contain noradrenaline. Many also contain neuropeptide Y. 2) **Cholinergic neurons** that probably originate in the sphenopalatine ganglia also innervate the cerebral vessles. **Postganglionic cholinergic neurones** on the blood vessels contain acetylcholine. Many also contain vasoactive intestinal peptide (VIP). These nerves end primarily on large arteries 3) **Sensory nerves** are found on more distal arteries. They have their cell bodies in the trigeminal ganglia and contain substance P, neurokinin A, and calcitonin gene-related peptide, which cause either vasodilation or vasoconstriction.

Answer 359

1) Plasma is passively filtered across the choroidal capillary endothelium 2) Secretion of water and ions across the choroidal epithelium provides for active control of CSF composition and quantity.

Answer 360

70-180mmH2O.

Answer 361

* Up to pressures well above 70-180 mm H2O, the rate of CSF **formation** is independent of intraventricular pressure * Absorption is proportional to the pressure. * At a pressure of **112 H2O** (which is the average normal CSF pressure), filtration and absorption are equal * Below a pressure of approx **68 mm H2O, absorption stops**.

Answer 362

* When the capacity for CSF reabsorption is decreased (external hydrocephalus, communicating hydrocephalus) * Fluid also accumulates proximal to the block and distends the ventricles when the foramens of Luschka and Magendie are blocked or there is an obstruction within the ventricular system (internal hydrocephalus, non-communicating hydrocephalus).

Answer 363

* When the skull is fractured and bone is driven into neural tissue (depressed skull fracture) * When the brain moves far enough to tear the delicate bridging veins from the cortex to the bone * When the brain is accelerated by a blow on the head and is driven against the skull or the tentorium at a point opposite where the blow was struck (contrecoup injury)

Answer 364

The tight junctions between the capillary endothelial cells in the brain and between the epithelial cells in the choroid plexus effectively prevent proteins from entering the brain and slow the penetration of some smaller molecules. This uniquely limited exchange of substances into the brain is referred to as the **blood-brain barrier**, which also refers to the barrier in the choroid epithelium between blood and CSF

Answer 365

Water, CO2 and O2 Lipid-soluble free forms of steroid hormones

Answer 366

The rapid passive penetration of CO2 contrasts with the regulated travnscellular penetration of H+ and HCO3- and has physiological significance in the regulation of respiration.

Answer 367

Its diffusion across the blood-brain barrier would be very slowly, but the rate of transport into the CSF is markedly enhanced by the presence of specific transporters, including the glucose transporter 1 (GLUT1)

Answer 368

A multidrug non-specific transporter in the apical membranes of the endothelial cells. This **P-glycoprotein** is a member of the family of ATP-binding cassette transporters that transport various proteins and lipids across cell membranes.

Answer 369

1) The **posterior pituitary** and the adjacent ventral part of the **median eminence** of the hypothalamus 2) The **area postrema** 3) The **organum vasculosum of the lamina terminalis** (OVLT, supraoptic crest) 4) The **subfornical organ** They are collectively referred to as the circumventricular organs

Answer 370

* It strives to maintain the constancy of the environment of the neurons in the CNS. * Protection of the brain from endogenous and exogenous toxins in the blood * Prevention of the escape of neurotransmitters into the general circulation

Answer 371

According to **Fick's principle**, the blood flow of any organ can be measured by determining the amount of a given substance (Q) removed from the bloodstream by the organ by unit of time and dividing that value by the difference between the concentration of the substance in arterial blood and the concentration in the venous blood. This can be applied clinically using inhaled nitrous oxide (**Kety method**)

Answer 372

* ICP * Local constriction and dilation of cerebral arterioles * Mean arterial pressure at brain level * Viscosity of blood * Mean venous pressure at brain level

Answer 373

Because brain tissue and spinal fluid are essentially incompressible, the volume of blood, spinal fluid and brain in the cranium at any time must be relatively constant

Answer 374

The cerebral vessels are compressed.

Answer 375

* Any change in venous pressure promptly causes a similar change in intracranial pressure. * Thus, a rise in venous pressure decreases cerebral blood flow both by decreasing the effective perfusion pressure and by compressing the cerebral vessels. * This relationship helps compensate for changes in arterial blood pressure at the level of the head.

Answer 376

* If the body is accelerated upward, blood moves toward the feet and arterial pressure at the level of the head decreases. However, venous pressure also falls and ICP falls, so the pressure on the vessels decreases and blood flow is much less severely compromised than it would be. * Conversely, during acceleration downward, force acting toward the head increases arterial pressure at head level, but ICP also rises, so that the vessels are supported and do not rupture. * The cerebral vessels are protected during the straining associated with defecation or delivery in the same way

Answer 377

65-140 mm Hg

Answer 378

* **Noradrenergic discharge** occurs when the **blood pressure** is markedly **elevated**. This reduces the resultant passive **increase in blood flow** and helps protects the blood-brain barrier. Thus, vasomotor discharges affect autoregulation * With **sympathetic stimulation**, the constant-flow, or plateau, part of the **pressure-flow curve is extended to the right**; that is, greater increases of pressure can occur without an increase in flow. * On the other hand, the vasodilator hydralazine and the ACE inhibitor captopril reduce the length of the plateau

Answer 379

Glutamate entering the brain associates with ammonia and leaves as glutamine. The glutamate-glutamine conversion in the brain - the opposite of the reaction in the kidney that produces some of the ammonia entering the tubules - serves as a detoxifying mechanism to keep the brain free of ammonia

Answer 380

From the sinuses behind two of the cusps of the aortic valve at the root of the aorta.

Answer 381

* Through the coronary sinus and anterior cardiac veins. * In addition, there are other vessels that empty directly into the heart chambers. There include **arteriosinusoidal vessles**, sinusoidal capillary-like vessels that connect to the chambers; **thesbian veins** that connect capillaries to the chambers; and a few **arterioluminal vessels** that are small arteries draining directly into the chambers

Answer 382

They are compressed

Answer 383

* The pressure inside the left ventricle is slightly high than in the aorta during systole. * Consequently, flow occurs in the arteries supplying the subendocardial portion of the left ventricle only during diastole, although the force is suffieciently dissipated in the more superficial portions of the left ventricular myocardium to permit some flow in this region throughout the cardiac cycle.

Answer 384

Because diastole is short when the heart rate is high, LV coronary flow is reduced during tachycardia

Answer 385

The pressure differential between the aorta and the right ventricle, and the differential between the aorta and the atria, are somewhat greater during systole than during diatsole. Consequently, coronary flow in these parts of the heart is not appreciable reduced during systole

Answer 386

Because no blood flow occurs during systole in the subendocardial portion of the left ventricle, this region is prone to ischaemic damage and is the most common site of MI

Answer 387

Blood flow to the left venticle is decreased in patients with AS because the pressure in the left ventricle must be much higher that that in the aorta to eject the blood. Consequently, the coronary vessels are severely compressed during systole

Answer 388

Coronary flow is decreased when the aortic diastolic pressure is low. The rise in venous pressure in conditions such as heart failure reduced coronary flow because it decreases effective coronary perfusion pressure.

Answer 389

About 250mL/min (5% of the cardiac output)

Answer 390

Lp(a) has an outer coat consisting of apo(a). It interferes with fibrinolysis by down-regulating plasmin generation, increasing the forming of atherosclerotic plaques

Answer 391

* Lack of O2 * Increased local concentrations of CO2, H+, K+, lactate, prostaglandins, adenine nucleotides and adenosine

Answer 392

* The coronary arterioles contain **α-adrenergic** receptors, which mediate **vasoconstriction** * The coronary arterioles also contain **β-adrenergic** receptors, which mediate **vasodilation**.

Answer 393

* Activity in the noradrenergic nerves to the heart and injections of noradrenaline cause coronary vasodilation. * However, noradrenaline increases the heart rate and force of cardiac contraction, and the vasodilation is due to production of vasodilator metabolites in the myocardium secondary to the increase in its activity.

Answer 394

* When the systemic blood pressure falls, the overall effect of the reflex **increase in noradrenergic discharge** is **increased coronary blood flow** secondary to the metabolic changes in the myocardium at a time when the cutaneous, renal and splanchnic vessels are constricted. * In this way, the circulation of the heart is preserved when flow to other organs is compromised.

Answer 395

When a pointed object is drawn lightly over the skin, the stroke line becomes pale (white reaction). the mechanical stimulus apparently initiates contraction of the precapillary sphincters, and blood drains out of the capillaries and small veins. The response appears in about 15 seconds.

Answer 396

When the skin is stroked firmly with a pointed instrument, the triple reaction takes place 1) **Red reaction** - there is reddening at the site that appears in about 10 secs. This is due to capillary dilation, a direct response of the capillaries to pressure. 2) The **wheal** follows the red reaction in a few minutes by local swelling and diffuse, mottled reddening around the injury. It is due to increased permeability of the capillaries and postcapillary venules, with consequent extravasation of fluid. 3) The redness spreading out from the injury (**flare**) is due to arteriolar dilation

Answer 397

The flare is absent in locally anaesthetised skin and in denervated skin after the sensory nerves have degenerated, but it is present immediately after nerve block or section above the site of the injury.

Answer 398

* It is an **axon reflex**, a response in which impulses initiated in sensory nerves by the injury are relayed antidromically down other branches of the sensory nerve fibres. * The transmitter released at the central termination of the sensory C fiber neurons is substance P, and substance P and CGRP are present in all parts of the neurons. * Both dilate arterioles and, in addition, substance P causes extravasation of fluid

Answer 399

* It is an increase in the amount of blood in a region when its circulation is reestablished after a period of occlusion. * When the blood supply to a limb is occluded, the cutaneous arterioles below the occlusion dilate. * When the circulation is reestablished, blood flowing into the dilated vessels makes the skin become fiery red. * O₂ in the atmosphere can diffuse a short distance through the skin, adn reactive hyperemia is prevented if the circulation of the limb is occluded to an atmosphere of 100 O₂.

Answer 400

* When the body temperature rises during exercise, the cutaneous blood vessels dilate in spite of continuing noradrenergic discharge in other parts of the body. * Dilation of cutaneous vessels in response to a rise in hypothalamic temperature overcomes other reflex activity. * Cold causes cutaneous vasoconstriction; however, with severe cold, superficial visodilation may supervene. This vasodilation is the cause of the ruddy complexion seen on a cold day.

Answer 401

* Noradrenergic nerve stimulation and circulating epinephrine and norepinephrine constrict cutaneous blood vessels. * No know vasodilator nerve fibers extend to the cutaneous vessles, and thus vasodilation is brought about by a decrease in constrictor tone as well as the local production of vasodilator metabolites.

Answer 402

1.2 - 1.3L of blood per minute Just under 25% of cardiac output

Answer 403

Because the kidney filters plasma, the **renal plasma flow** equals the amount of a substance excreted per unit time divided by the renal arteriovenous difference as long as the amount of the red cells is unaltered during passage through the kidney. Any excreted substance can be used if its concentration in arterial and renal venous plasma can be measured.

Answer 404

* RPF can be measured by infusing **p-aminohippuric acid** (PAH) and determing its urine and plasma concentrations. * PAH is filtered by the glomeruli and secreted by the tubular cells, so that its **extraction ratio** (arterial concentration minus renal venous concentration divided by arterial concentration) is high. * It has therefore become commonplace to calculate the 'RPF' by dividing the amount of PAH in the urine by the plasma PAH level. * Peripheral venous plasma can be used because its PAH concentration is essentially identical to that in the arterial plasma reaching the kidney. * The value obtained should be called the **effective renal plasma flow**. * ERPF averages about **652mL/min**.

Answer 405

Renal blood flow is the renal plasma flow multiplied by 1 divided by 1 minus the haematocrit

Answer 406

* When the mean systemic arterial pressure is 100mmHg, the **glomerular capillary pressure is about 45mmHg**. * The pressure drop across the glomerulus is only 1-3mmHg, but a further drop occurs in the efferent arteriole so that the pressure in the **peritubular capillaries is about 8mmHg**. * The pressure in the renal vein is about 4mmHg.

Answer 407

* **Noradrenaline** constricts the renal vessels, with the greatest effect being exerted on the interlobular arteries and afferent arterioles * **Angiotensin II** exerts a constrictor effect on both the afferent and efferent arterioles. * **Dopamine** is made in the kidney and causes renal vasodilation and natriuresis. * **Prostaglandins** increase blood flow in the renal cortex and decrease blood flow in the renal medulla * **Acetylcholine** also produces renal vasodilation * A **high-protein diet** raises glomerular capillary pressure and increases renal blood flow

Answer 408

* It increases renin secretion by direct action of released noradrenaline on β1-adrenergic receptors on the juxtaglomerular cells. * It increases Na+ reabsorption, probably by a direct action on norephinephrine on renal tubular cells. * It causes increased sensitivity of the granular cells in the juxtaglomerular apparatus. * At the highest thresold, it causes renal vasoconstriction with decreased glomerular filtration and renal blood flow

Answer 409

* It causes a marked decrease in renal blood flow. * This effect is mediated by α1-adrenergic receptors and to a lesser extent by postsynaptic α2-adrenergic receptors.

Answer 410

When systemic blood pressure falls, the vasoconstrictor response produced by decreased discharge in the baroreceptor nerves includes renal vasoconstriction

Answer 411

When the kidney is perfused at moderate pressures, the renal vascular resistance varies with the pressure so that renal blood flow is relatively constant

Answer 412

Renal autoregulation is present in denervated and in isolated, perfused kidneys but is prevented by the administation of drugs that paralyse vascular smooth muscle.

Answer 413

* It is probably produced in part by a direct contractile response to stretch of the smooth muscle of the afferent arteriole. * NO may also be involved * At low perfusion pressures, angiotension II constricts the efferent arterioles, thus maintaining the GFR.

Answer 414

Filtration of large volumes of blood through the glomeruli, so it is not surprising that the renal cortical blood flow is relatively great and little oxygen is extracted from the blood.

Answer 415

Maintenance of the osmotic gradient in the medulla requires a relatively low blood flow. * **Cortical blood flow** - 5mL/g/minute * **Outer medulla blood flow** - 2.5mL/g/minute * **Inner medulla blood flow** - 0.6mL/g/minute

Answer 416

The product of the cardiac output and the arterial oxygen concentration.

Answer 417

* The amount of O2 entering the lungs * The adequacy of pulmonary gas exchange * The blood flow to the tissue * The capacity of the blood to carry oxygen * Cardiac output * The degree of constricution of the vascular bed in the tissue

Answer 418

* The amount of dissolved O2 * The amount of haemoglobin in the blood * The affinity of the Hb for O2

Answer 419

* A protein made of four subunits, each of which contains a **heme** moiety attached to a polypeptide chain. * In normal adults, most of the Hb molecules contain two α and two β chains.

Answer 420

* Heme is a porphyrin ring complex that includes one atom of ferrous iron. Each of the four iron atoms in Hb can reversibly bind one O2 molecules. * The iron stays in the ferrous state, so that the reaction is oxygenation. * The reaction is rapid, requiring less than 0.01 seconds.

Answer 421

* In deoxyhaemoglobin, the globin units are tightly bound in a **tense (T) configuration**, which reduces the affinity of the molecule for O2. * When O2 is first bound, the bonds holding the globin units are released, producing a **relaxed (R) configuration**, which exposes more O2 binding sites. * The net result is a 500-fold increase in O2 affinity. The transition from one state to another has been calculated to occur about a trillion times in the life of a red blood cell.

Answer 422

* It relates percentage saturation of the O₂ carrying power of haemoglobin (abbreviated as SaO₂) to the PO₂. * This curve has a characteristic sigmoid shape due to the T-R configuration interconversion. * Combination of the first heme in the Hb molecule with O₂ increases the affinity of the second heme for O₂, and oxygenation of the second increases the affinity of the third etc. * Especially note that small changes at low PO₂ lead to large changes in SaO₂.

Answer 423

* When blood is equilibrated with 100% O₂, the normal haemoglobin becomes 100% saturated. When fully saturated, each gram of normal haemoglobin contains 1.39mL of O₂. * However, blood normally contains small quantites of inactivate haemoglobin, and the measured value is slightly lower. * Using the traditional estimate of saturated Hb in vivo, 1.34mL of O₂, the Hb concentration in normal blood is about 15g/dL. Therefore 1dL of blood contains 20.1mL (1.34mL x 15) of O₂ bound to Hb when the Hb is 100% saturated. * The amount of dissolved O₂ is a linear function of the PO₂. - 0.0003mL/dL blood/ mmHgPO₂

Answer 424

**Capillaries** - about 97.5% saturated with O₂ (PO₂ = 100mmHg)

Answer 425

* **Systemic arterial blood** - 97% saturated * 19.8mL of O2 per dL: 0.29mL in solution and 19.5mL bound to Hb.

Answer 426

* Hb is 75% saturated * Total O2 content is about 15.2 mL/dL: 0.12mL in solution and 15.1mL bound to Hb

Answer 427

* At rest the tissues remove about **4.6mL** of O2 from each dL of blood passing through them; 0.17mL of this from solution and the remainder from Hb. * In this way, 250mL of O2 per minute is transported from the blood to the tissues at rest

Answer 428

* The **pH, temperature** and the concentration of **2,3-diphosphoglycerate (DPG; 2,3-DPG)**. * A rise in temperature or a fall in pH shifts the curve to the right. When the curve is shifted in this direction, a higher PO₂ is required for Hb to bind a given amount of O₂. * Conversely, a fall in temperature or a rise in pH shifts the curve to the left, and a lower PO₂ is required to bind a given amount of O₂.

Answer 429

* A convenient index for comparison of shifts of the curve is P50. * The PO2 at which Hb is half-saturated with O2. * The higher the P50, the lower the affinity of Hb for O2.

Answer 430

* The decrease in O2 affinity of Hb when the pH falls is called the **Bohr effect** and is closely related to the fact that deoxygenated Hb binds H+ more actively than does oxygenated Hb. * The pH of blood falls as its CO2 content increases, so that when the PCO2 rises, the curve shifts to the right and the P50 rises. * Most of the unsaturatation of Hb that occurs in the tissues is secondary to the decline in the PO2, but an extra 1-2% unsaturation is due to the rise in PCO2 and consequent shift of the dissociation curve to the right.

Answer 431

* It is formed from 3-phosphoglyceraldehyde, which is a product of glycolysis via the **Embden-Meyerhof pathway** * It is a highly charged anion that bind to the β chains of deoxyhaemoglobin. * One mole of deoxyhaemoglobin binds 1 mol of 2,3-DPG. * In this equilibrium, an increase in the concentration of 2,3-DPG shifts the reaction to the right, causing more O2 to be liberated.

Answer 432

* Because acidosis inhibits red cell glycolysis, the 2,3-DPG concentration falls when the pH is low * Conversely, thyroid hormones, growth hormones, and androgens can all increase the concentration of 2,3-DPG and the P50. * Exercise has been reported to produce an increase in 2,3-DPG within 60 mintues. The P50 is also increased during exercise because the temperature rises in active tissues and CO₂ and metabolites accumulate, lowering the pH.

Answer 433

* The **upper airway** consists of the entry systems, the nose/nasal cavity and mouth that lead into the pharynx. The larynx extends from the lower part of the pharynx to complete the upper airway * The **conducting airway** begins at the trachea and branches dichotomously to greatly expant the surface area of the tissue in the lung. The first 16 generations of passages form the conducting zone of the airways that transports gas from and to the upper airway - bronchi, bronchioles and terminal bronchioles. * The **alveolar airway** consists of the last seven generations of airway divisions where gas exchange occurs - made up of transitional and respiratory bronchioles, alveolar ducts and alveoli.

Answer 434

1) filtering out large particulates to prevent them from reaching the conducting and alveolar airways 2) serving to warm and humidify air as it enters the body

Answer 435

* They enter the conducting airway, settle on mucous membranes in the nose and pharynx. * Because of their momentum, they do not follow the airstream as it curves downward into the lungs, and they impact on or near the **tonsils** and **adenoids**, large collections of immunologically active lymphoid tissue in the back of the pharynx.

Answer 436

* The mucosal epithelium is attached to a thin basement membrane, and beneath this, the lamina propria. Collectively, these are referred to as the "airway mucosa" * Smooth muscle cells are found beneath the epithelium and an enveloping connective tissue is likewise interspersed with cartilage that is more predominant in the portions of the conducting airway of greater caliber.

Answer 437

It is organised as pseudostratified epithelium and contains several cell types, including ciliated and secretory cells (e.g goblet cells and glandular acini) that provide key components for airway innate immunity, and basal cells that can serve as progenitor cells during injury.

Answer 438

* Secretory glands are absent from the epithelium of the bronchioles and terminal bronchioles, smooth muscle plays a more prominent role and cartilage is largely absent from the underlying tissue. * Club cells, nonciliated cuboidal epithelial cells that secrete important defense markers and serve as progenitor cells after injury, make up a large portion of the epithelial lining in the latter portions of the conducting airway

Answer 439

* Secretory immunoglobulins (IgA), collectins (including surfactant protein (SP) -A and SP-D), defensins and other peptides and proteases, ROS and RNS are all generated by airway epithelial cells * These secretions can act directly as antimicrobials to help keep the airway free of infection. * Airway epithelial cells also secrete a variety of chemokines and cytokines that recruit traditional immune cells and other immune effector cells to site of infections.

Answer 440

* The epithelium of the respiratory passages from the anterior third of the nose to the beginning of the respiratory bronchioles is ciliated. * The cilia are bathed in a periciliary fluid where they typically beat at rates of 10-15 Hz. * On top of the periciliary layer and the beating cilia rests a mucus layer, a complex mixture of proteins and polysaccharides secreted from specialised cells, glands, or both in the conducting airway. * This combination allows for the trapping of foreign particles (in the mucus) and their transport out of the airway (powered by ciliary beat).

Answer 441

At a rate of at least 16mm/minute

Answer 442

* When ciliary motility is defective, as can occur in smokers, or as a result of other environmental conditions or genetic deficiencies (CF), mucous transport is virtually absent. * This can lead to chronic sinusitis, recurrent lung infections and bronchiectasis.

Answer 443

* Nerve cells in the airways sense mechanical stimuli or the presence of unwanted substances in the airways such as inhaled dusts, cold air, noxious gases and cigarette smoke. * These neurons can signal the respiratory centers to contract the respiratory muscles and initiate sneeze or cough reflexes. * The receptors show rapid adaptation when they are continuously stimulated to limit sneeze and cough under normal conditions.

Answer 444

The β2-adrenergic receptors help mediate bronchodilation. They also increase bronchial secretions (e.g. mucus), while α1-adrenergic receptors inhibit secretions.

Answer 445

The total cross-sectional area in the alveoli is 11,800cm². Consequently, the velocity of airflow in the small airways declines to very low values.

Answer 446

* **Type I cells** are flat cells with large cytoplasmic extensions and are the primary lining cells of the alveoli, covering approx 95% of the alveolar epithelial surface area. * **Type II cells (granular pneumocytes)** are thicker and contain numerous lamellar inclusion bodies. Although these cells make up only 5% of the surface area, they represent approx 60% of the epithelial cells in the alveoli.

Answer 447

* They are important in alveolar repair as well as other cellular physiology. * One prime function is the production of **surfactant**.

Answer 448

* Typical **lamellar bodies**, membrane-bound organelles containing whorls of phospholipid, are formed in these cells and secreted into the alveolar lumen by exocytosis. * Tubes of lipid called **tubular myelin** form from the extruded bodies, and the tubular myelin in turn forms a phospolipid film * Following secretion, the phospholipids of surfactant line up in the alevoli with their hydrophobic fatty acid tails facing the alveolar lumen.

Answer 449

* The surfactant layer plays an important role in maintaining alveolar structure by reducing surface tension. * Surface tension is inversely proportional to the surfactant concentration per unit area. * The surfactant molecules move further apart as the alveoli enlarge during inspiration, and surface tension increases, whereas it decreases when they move closer together during expiration

Answer 450

In most area, air and blood are separated only by the alveolar and the capillary endothelium, so they are about 0.5μm apart.

Answer 451

* Pulmonary alveolar macrophages (PAMs) * Lymphocytes * Plasma cells * Neuroendocrine cells * Mast cells

Answer 452

* Like other macrophages, they originally come from the bone marrow * PAMs are actively phagocytic and ingest small particles that evade the mucociliary escalator and reach the alveoli. * They also help process inhaled antigens for immunologic attack, and they secrete substances that attract granulocytes to the lungs as well as substances that stimulate granulocyte and monocyte formation in the bone marrow * PAM function can also be detrimental - when they ingest large amounts of the substances in cigarette smoke or other irritants, they may release lysosomal products into the extracellular space to cause inflammation.

Answer 453

The **pleural cavity** and its infoldings serve as a lubricating fluid/area that allows for lung movement within the thoracic cavity

Answer 454

It is subatmospheric. * The lungs are stretched when they expand at birth, at the end of quiet expiration their tendency to recoil from the chest wall is just balanced by the tendency of the chest wall to recoil in the opposite direction. * If the chest wall is opened, the lungs collapse; and if the lungs lose their elasticity, the chest expands and becomes barrel-shaped

Answer 455

* It is an active process. * The contraction of the inspiratory muscles increases intrathoracic volume. * The intrapleural pressure at the base of the lungs, which is normally about -2.5mmHg at the start of inspiration, decreases to about -6mmHg. * The lungs are pulled into a more expanded position. The pressure in the airway becomes slightly negative, and air flows into the lungs.

Answer 456

* At the end of inspiration, the lung recoil begins to pull the chest back to the expiratory position, where the recoil pressures of the lungs and chest wall balance. * The pressure in the airway becomes slightly positive, and air flows out of the lungs. * Expiration during quiet breathing is passive. However, some contraction of the inspiratory muscles occurs in the early part of expiration. This contraction exerts a breaking action on the recoil forces and slows expiration.

Answer 457

-30mmHg, producing correspondingly greater degrees of lung inflation. When ventilation is increased, the extent of lung deflation is also increased by active contraction of expiratory muscles that decrease intrathoracic volume.

Answer 458

Direct measurement of gas intake and output.

Answer 459

A patient's lung function for purposes of comparison with a normal population, or with previous measures from the same patient.

Answer 460

**Tidal volume** - the amount of air that moves into the lungs with each inspiration (or the amount that moves out with each expiration) during quiet breathing Typical values for TV are on the order of 500-750mL

Answer 461

The air inspired with a maximal inspiratory effect in excess of the TV is the **inspiratory reserve volume**. Typically around 2L

Answer 462

The volume expelled by an active expiratory effort after passive expiration is the **expiratory reserve volume** - around 1L

Answer 463

The air left in the lungs after a maximal expiratory effort if the **residual volume** Typical value around 1.3L

Answer 464

The inspiratory reserve volume + tidal volume + expiratory reserve volume + residual volume Typical value around 5L

Answer 465

It refers to the maximum amount of air expired from the fully inflated lung, or maximum inspiratory level. TV + IRV + ERV Typically around 3.5L

Answer 466

The maximum amount of air inspired from the end-expiratory level (IRV + TV). Typically around 2.5L

Answer 467

The volume of air remaining after expiration of a normal breath (RV + ERV) Typically around 2.5L

Answer 468

The largest amount of air that can be expired after a maximal inspiratory effort. It is frequently measured clinically as an index of pulmonary function

Answer 469

The forced expiratory volume expired during the first second of forced expiration

Answer 470

To classify the type of airway disease. * Patients with obstructive or restrictive diseases can have reduced FVC. * Patients with obstructive disease tend to show a slow, steady slope to the FVC, resulting in a small FEV1 * Patients with restrictive disease tend to be fast at first then quickly level out to approach FVC. * Obstructive disorders result in a marked decrease in both FVC and FEV1/FVC, whereas restrictive disorders result in a loss of FVC without loss in FEV1/FVC.

Answer 471

500mL/breath x 12 breaths/minute - normally around 6L

Answer 472

* The largest volume of gas that can be moved into and out of the lungs in 1 minute by voluntary effort * Typically this is measured over a 15 second period and propogated to a minute * Normal values range from 140L/min-180L/min for a healthy adult man

Answer 473

The change in pressure (ΔP) from the alveoli to the mouth divided by the change in flow rate.

Answer 474

* Airway resistance is significanttly increased as lung volume is reduced * Also, bronchi and bronchioles significantly contribute to airway resistance * Thus, contraction of the smooth muscle that lines the bronchial airways will increase airway resistance, and make breathing more difficult

Answer 475

* In the upright position, ventilation per unit lung volume is **greater at the base** of the lung that at the apex. * The reason for this is that at the start of inspiration, **intrapleural pressure is less negative at the base than at the apex**, and since the intrapulmonary intrapleural pressure difference is less than at the apex, the **lung is less expanded** * Conversely, at the apex, the lung is more expanded; that is, the percentage of maximum lung volume is greater * Because of the stiffness of the lung, the **increase in lung per volume per unit increase in pressure is smaller when the lung is initially more expanded**, and ventilation is consequently greater at the base

Answer 476

* Blood flow is also **greater at the base** of the lung than at the apex. * The relative change in blood flow from the apex to the base is greater than the relative change in ventilation, so the **ventilation/perfusion ratio is low at the base and high at the apex.**

Answer 477

They have been attributed to gravity: they tend to disappear in the supine position, and the weight of the lung would be expected to create pressure at the base in the upright position. However, the inequalities of ventilation and blood flow in humans were found to persist to a remarkable degree in the weightlessness of space. Therefore, other factors also play a role in producing the inequalities.

Answer 478

* Because gaseous exchange occurs only in the terminal portions of the airways, the gas that occupies the rest of the respiratory system is not available for gas exchange with pulmonary capillary blood. * Normally, the volume (in mL) of this **anatomic dead space** is approximately equal to the body weight in pounds.

Answer 479

The **alveolar ventilation**, i.e., the amount of air reaching the alveoli per minute, is less than the RMV. Note that because of the dead space, rapid shallow breathing produces much less alveolar ventilation than slow deep breathing at the RMV

Answer 480

* **Anatomic dead space** - respiratory system volume exclusive of alveoli * **Total (physiologic) dead space** - volume of gas not equilibrating with blood; i.e. wasted ventilation

Answer 481

* In healthy individuals, the two dead spaces are identical and can be estimated by body weight * However, in disease states, no exchange may take place between the gas in some of the alveoli and the blood, and some of the alveoli may be overventilated. * The volume of gas in non-perfused alveoli and any volume of air in the alveoli in excess of that necessary to arterialise the blood in the alveolar capillaries is part of the dead space gas volume

Answer 482

* The anatomic dead space can be measured by analysis of the single-breath N₂ curves. * From mid-inspiration, the patient takes as deep a breath as possible of pure O₂, then exhales steadily while the N₂ content of the expired gas is continuously measured.

Answer 483

* **Phase I** - the initial gas exhaled is the gas that filled the dead space and that consequently contains no N₂. * This is following by a mixture of dead space and alveolar gas (**phase II**) and then by alveolar gas (**phase III**). * The volume of the dead space is the volume of gas expired from inspiration to the midpoint of Phase II * Phase III terminates at the **closing volume** (CV) and is followed by **phase IV**, during which the N₂ content of the expired gas is increased;

Answer 484

The closing volume is the lung volume above residual volume at which airways in the lower, dependent parts of the lungs begin to close off because of the lesser transmural pressure in these areas.

Answer 485

The gas in the upper portion of the lungs is richer in N₂ than the gas in the lower, dependent portions because the alveoli in the upper portions are more distended at the start of the inspiration of O₂ and, consequently, the N₂ in them is less diluted with O₂

Answer 486

The total dead space can be calculated from the PCO₂ of expired air, the PCO₂ of arterial blood and the tidal volume. * Vt - tidal volume * PECO₂ - PCO₂ of the expired gas * PaCO₂ - arterial PCO₂ * Vd - dead space * PICO₂ - PCO₂ of inspired air. ## Footnote PICO₂ x Vd is so small that it can often be ignored.... so Vd = Vt - (PECO₂ x Vt)/(PaCO₂)

Answer 487

* **PCO₂** is an average of gas from different alveoli in proportion to their ventilation regardless of whether they are perfused. * **PaCO₂** is gas equilibrated only with perfused alveoli, and consequently, in individuals with underperfused alveoli, is greater than PCO₂

Answer 488

* Unlike liquids, gases expand to fill the volume available to them, and the volume occupied by a given number of gas molecules at a given temperature and pressure is the same regardless of the composition of the gas. * **Partial pressures** are frequently used to describe gases in respiration. The pressure exerted by any one gas in a mixture of gases (its partial pressure) is equal to the total pressure times the fraction of the total amount of gas it represents.

Answer 489

Its temperature and number of moles occupying a certain volume

Answer 490

* 20.98% O2 * 0.04% CO2 * 78.06 N2 * 0.92% other inert constituents such as argon and helium

Answer 491

* The barometric pressure (Pb) at sea level is 760 mmHg (1 atmosphere) * The partial pressure of O₂ in dry air is therefore 0.21 x 760 or 160mmHg at sea level * The PN₂ is 0.79 x 760 or 600mmHg * The PCO₂ is 0.0004 x 760 or 0.3 mmHg

Answer 492

* The water vapour in the air reduced the percentages of gases, and therefore the partial pressures, to a slight degree. * The partial pressures at sea levels of gases in the air reaching the lungs are: * PO₂ - 150mmHg * PCO₂ - 0.3mmHg * PN₂ - 563mmHg

Answer 493

* Gas diffuses from areas of high pressure to areas of low pressure, with the rate of diffusion depending on the concentration gradient and the nature of the barrier between the two areas. * When a mixture of gases is in contact with, and permitted to, equilibrate with a liquid, each gas in the mixture dissolves in the liquid to an extent determined by its partial pressure and its solubility in the fluid * The partial pressure of a gas in a liquid is the pressure that, in the gaseous phase in equilibrium with the liquid, would produce the concentration of gas molecules found in the liquid

Answer 494

Across the thin alvelocapillary membrane made up of the pulmonary epithelium, the capillary endothelium, and their fused basement membranaes

Answer 495

Their reaction with substances in the blood. * Nitrous oxide does not react and reaches equilibrium in about 0.1 seconds. The amount of N₂O taken up is not limited by diffusion but by the amount of blood flowing through the capillaries; it is **flow-limited** * CO is taken up by Hb at such a high rate that the PCO in the capillaries stays very low and equilibrium is not reached in the 0.75 seconds - it is **diffusion-limited** * O₂ is an intermediate between N₂O and CO; it is taken up by Hb but much less avidly than CO, and reaches equilibrium in about 0.3 seconds. Thus, its uptake is **perfusion-limited**.

Answer 496

The diffusing capacity for a given gas is directly proportional to the surface area of the alveolar capillary membrane and inversely proportional to its thickness.

Answer 497

* An an index of diffusing capacity because its uptake is diffusion-limited. * DLCO is proportional to the amount of CO entering the blood (VCO) divided by the partial pressure of CO minus the partial pressure of CO in the blood entering the pulmonary capillaries (which in healthy people in zero)

Answer 498

* The normal value of DLCO at rest is about 25mL/min/mmHg. * It increases up to threefold during exercise because of capillary dilation and an increase in the number of active capillaries.

Answer 499

* The PO₂ of alveolar air is normally 100 mmHg * The PO₂ of the blood entering the pulmonary capillaries is 40mmHg * The diffusing capacity for O₂, like that for CO at rest, is about 25 mL/min/mmHg * The PO₂ of blood is raised to 97mmHg, just under the alveolar PO₂.

Answer 500

* The PCO₂ of venous blood is 46 mmHg * The PCO₂ of alveolar air is 40mmHg * CO₂ diffuses from the blood into the alveoli along this gradient. CO₂ passes through all biological membranes with ease, and the diffusing capacity of the lung for CO₂ is much greater than the capacity for O₂

Answer 501

* Theoretically, all but the first 150mL expired from a healthy 150lb man (ie, the dead space) with each expiration is the gas that was in the alveoli (alveolar air), but some mixing always occurs at the interface between the dead space gas and the alveolar air. A later portion of expired air is therefore the portion taken for analysis. * Using modern apparatus, it is possible the collect the last 10mL expired during quiet breathing. * The composition of alveolar gas is compared with that of inspired and expired gas.

Answer 502

* It can be used to work of PAO₂ * FIO₂ is the fraction of O₂ molecules in the dry gas * PIO₂ is the inspired PO₂ * R is the respiratory exchange radio, that is, the flow of CO₂ molcules across the alveolar membrane per minute divided by the flow of O₂ molecules across the membrane per minute

Answer 503

1) **Hypoxemia** (sometimes termed **hypoxic hypoxia**, in which the PO₂ of the arterial blood is reduced 2) **Anaemic hypoxia**, in which the arterial PO₂ is normal but the amount of haemoglobin available to carry O₂ is reduced 3) **Ischaemic** or **stagnant hypoxia**, in which the blood flow to a tissue is so low that adequate O₂ is not delivered to it despite a normal PO₂ and haemoglobin concentration 4) **Histotoxic hypoxia**, in which the amount of O₂ delivered to a tissue is adquate but because of a toxic agent, the tissue cells cannot make use of the O₂ supplied to them.

Answer 504

Reduced arterial PO₂. It is a problem in normal individuals at high altitudes and is a complication of pneumonia and a variety of other diseases of the respiratory system.

Answer 505

* The composition of air stays the same, but the total barometric pressure falls with increasing altitude, and thus, the PO₂ also falls. * At 3000m above sea level, the alveolar PO₂ is about 60mmHg and there is enough hypoxic stimulation of the chemoreceptors under normal breathing to cause increase ventilation * As one ascends higher, the alveolar PO₂ falls less rapidly and the alveolar PCO₂ declines because of the hyperventilation. * The resulting fall in arterial PCO₂ produces respiratory alkalosis.

Answer 506

* A number of compensatory mechanisms operate over a period of time to increase altitude tolerance (**acclimatisation**) * In an unacclimatised person, mental symptoms such as irritability appear at about **3700m**. * At **5500m**, the hypoxic symptoms are severe * At altitudes about **6100m** (20,000feet), consciousness is usually lost.

Answer 507

* Hypoxia causes the production of transcription factors (hypoxia-inducible factors; HIFs). These are make up of α and β subunits. * In normally oxygenated tissues, the α subunits are rapidly ubiquinated and destroyed. * However, in hypoxic cells, the α subunits dimerise with β subunits, and the dimers activate genes that produce several proteins including angiogenic factors and erythropoietin, among others

Answer 508

* In hypoxymia and the other generalised forms of hypoxia, the brain is affected first. * A sudden drop in the inspired PO₂ to less than 20mmHg, which occurs, for example, when cabin pressure is suddenly lost in a plane flying above 16,000m, causes LOC in 10-20 seconds and death in 4-5 minutes. * Less severe hypoxia causes a variety of mental aberrations similar to those produced by alcohol: impaired judgement, drowsiness, dulled pain sensibility, excitement, disorientation, loss of time sense, and headache. Other symptoms include anorexia, nausea, vomiting, tachycarida, and when the hypoxia is severe, HTN. * The rate of ventilation is increased in proportion to the severity of the hypoxia of the carotid chemoreceptor cells.

Answer 509

The partial pressure of water vapour in the alveolar air is constant at 47mmHg, and that of CO₂ is normally 40mmHg, so that the lowest barometric pressure at which a normal alveolar PO₂ lowers the alveolar PCO₂ somewhat, but the maximum alveolar PO₂ that can be attained when breathing 100% O₂ at the ambeint barometric pressure of 100 mmHg at 13,700m is approx 40 mmHg.

Answer 510

* Acclimatisation to altitude is due to the operation of a variety of compensatory mechanisms. * The **respiratory alkalosis** produced by the **hyperventilation** shifts the oxygen-haemoglobin dissociation curve to the left, but a concomitant increase in red blood cell 2,3-DPG tends to decrease the O₂ affinity of Hb. * The net effect is a small increase in P₅₀. * The decrease in O₂ affinity makes more O₂ available to the tissues. * However, the value of the increase in P₅₀ is limited because when the arterial PO₂ is markedly reduced, the decreased O₂ affinity also interfered with O₂ uptake by Hb in the lungs.

Answer 511

* The initial ventilatory response to increased altitude is relatively small, because the alkalosis tends to counteract the stimulating effect of hypoxia. * However, ventilation steadily increases over the next 4 days because the active transport of H⁺ into CSF or possibly a developing lactic acidosis in the brain, causes a fall in CSF pH that increases the response to hypoxia. * After 4 days, the ventilatory response begins to decline slowly, but it takes years of residence at higher altitudes for it to decline to the initial level, if it is reached at all.

Answer 512

* Erythropoietin secretion increases promptly on ascent to high altitude and then falls somewhat over the following 4 days as the ventilatory response increases and the arterial PO₂ rises. * The increase in circulating RBCs triggered by the erythropoietin begins in 2-3 days and is sustained as long as the individual remains at high altitude.

Answer 513

* The mitochondria, which are the site of oxidative reactions, increase in number, and myoglobin increases, which facilititates the movement of O₂ into the tissues. * The tissue content of cytochromise oxidase also increases.

Answer 514

* This syndrome develops 8-24 hours after arrival at altitude and lasts 4-8 days. * It is characterised by headache, irritability, breathlessness, N&V * It's cause appears to be associated with cerebral oedema. The low PO₂ at high altitude causes arteriolar dilation, and if cerebral autoregulation does not compensate there is an increase in capillary pressure that favours increased transudation of fluid into brain tissue

Answer 515

* In **high-altitude cerebral edema**, the capillary leakage in mountain sickness progresses to frank brain swelling, with ataxia, disorientation, and in some cases coma and death due to herniation of the brain through the tentorium. * **High-altitude pulmonary oedema** is a patchy oedema of the lungs that is released to the marked pulmonary hypertension that develops at high altitude. It is thought that it occurs because not all pulmonary arteries have enough smooth muscle to constrict in response to hypoxia, and in the capillaries supplied by those arteries, the general rise in pulmonary arterial pressure causes a capillary pressure increase that disrupts their walls.

Answer 516

* They are all benefited by descent to lower altitude and by treatment with the diuretic acetazolamide. * This drug inhibits carbonic anhydrase and results in stimulated respiration, increased PaCO₂, and reduced formation of CSF. * When cerebral oedema is marked, large doses of glucocorticoids are often administered as well. * In high-altitude pulmonary oedema, prompt treatment with O₂ is essential - and, if available, use of a hyperbaric chamber

Answer 517

1) Those in which the gas exchange apparatus fails 2) Those such as congenital heart disease, in which large amounts of blood are shunted from the venous to the arterial side of the circulation, 3) Those in which the respiratory pump fails.

Answer 518

* Lung failure occurs when conditions such as pulmonary fibrosis produce alveolar-capillary block, or there if ventilation-perfusion imbalance * Pump failure can be due to fatigue of the respiratory muscles in conditions in which the work of breathing is increased or to a variety of mechanical defects such as PTx or bronchial obstruction that limit ventilation. * It can also be caused by abnormallities of the neural mechanisms that control ventilation, such as depression or the respiratory neurons in the medulla by morphine and other drugs

Answer 519

* When a cardiovascular abnormality such as interarterial septal defect permits large amounts of unoxygenated venous blood to bypass the pulmonary capillaries and dilute the oxygenated blood in the systemic arteries ("right-to-left shunt"), chronic hypoxaemia and cyanosis (**cyanotic congenital heart disease**) result. * Administration of 100% O₂ raises the O₂ content of alveolar air but has little effect on hypoxia due to venous-to-arterial shunts. This is because the deoyxgenated venous blood does not have the opportunity to get to the lung to be oxygenated.

Answer 520

Ventilation-perfusion imbalance.

Answer 521

* The ventilation-blood flow ratios in different parts of the lung determine the extent to which systemic arterial PO₂ declines. * If non-ventilated alveoli are perfused, the non-ventilated but perfused potion of the lung is in effect a right-to-left shunt, dumping unoxygenated blood into the left side of the heart. * Lesser degrees of ventilation-perfusion imbalance are more common. * When ventilation is not in balance with perfusion, O₂ exchange is compromised. Note, that underventilated alveoli (B) have a low alveolar PO₂, whereas the overventilated alveoli (A) have a high alveolar PO₂, which both have the same blood flow. * Consequently, the arterial blood is unsaturated.

Answer 522

* Hypoxia due to anaemia is not severe at rest unless the Hb deficiency is marked, because 2,3-DPG increases in the red blood cells. * However, anaemic patients may have considerable difficulty during exercise because of a limited ability to increase O₂ delivery to the active tissues.

Answer 523

* Because it reacts with haemoglobin to form **carboxyhaemoglobin (COHb)**, and COHb does not take up O₂. * The affinity of Hb for CO is 210 times its affinity for O₂ and COHb liberates CO very slowly. * An additional difficulty is that when COHb is present, the dissociation curve of the remaining HBO₂ shifts to the left, decreasing the amount of O₂ released.

Answer 524

* Because of the affinity of CO for Hb, progressive COHb formation occurs when the alveolar PCO is greater than 0.4 mmHg. * However, the amount of COHb formed depends on the duration of exposure to CO as well as the concentration of CO in the inspired air and the alveolar ventilation.

Answer 525

* CO is also toxic to the cytochromes in the tissues, but the amount of CO required to poison the cytochromes is 1000 times the lethal dose * Tissue toxicity thus plays no role in clinical CO poisoning.

Answer 526

* The symptoms of CO poisoning are those of any type of hypoxia, especially the headache and nausea, but there is little stimulation of respiration, since in the arterial blood, PO₂ remains normal and the carotid and aortic chemoreceptors are not stimulated * The cherry-red colour of COHb is visible in the skin, nail beds and mucous membranes. * The symptoms produced by chronic exposure to sublethal CO are those of progressive brain damage, including mental changes and, sometimes, a parkinsonism-like state.

Answer 527

* Treatment of CO poisoning consists of immediate termination of the exposure and adequate ventilation, by artifical respiration if required. * Ventilation with O₂ is preferable to ventilation with fresh air, since O₂ hastens the dissociation of COHb. * Hyperbaric oxygenation is useful in this condition.

Answer 528

* Ischaemic hypoxia, or stagnant hypoxia, is due to slow circulation and is a problem in organs such as the kidneys and heart during shock. * The liver and possibly the brain are damaged by ischaemic hypoxia in heart failure. * The blood flow to the lung is normally very large, and it takes prolonged hypotension to produce significant damage. * However, ARDS can develop when there is prolonged circulatory collapse.

Answer 529

* Hypoxia due to inhibition of tissue oxidative processes is most commonly the result of cyanide poisoning. * Cyanide inhibits cytochrome oxidase and possibly other ezymes * Methylene blue or nitrates are used to treat cyanide poisoning. They act by forming **methemoglobin**, which then reacts with cyanide to form **cyanmethemoglobin**, a non-toxic compound. * The extent of treatment with these compounds is, of course, limited by the amount of methemoglobin that can be safely formed.

Answer 530

* Administration of oxygen-rich mixtures in of very limited value in hypoperfusion, anaemic, and histotoxic hypoxia because all that can be accomplished in this way in an increase in the amount of dissolved O₂ in the arterial blood. * This is also true in hypoxaemia when it is due to shunting of unoxygenated venous blood past the lungs.

Answer 531

* Retention of CO₂ in the body (hypercapnia) initially stimulates respiration. * Retention of larger amounts produced such symptoms as confusion, diminished sensory acuity and, eventually, coma with respiratory depression and death due to depression of the CNS * In patients with these symptoms, the PCO₂ is markedly elevated and severe respiratory acidosis is present. * Large amounts of HCO₃^- are excreted, but more HCO₃^- is reabsorbed, raising the plasma HCO₃^- and partially compensating for the acidosis.

Answer 532

* CO₂ is so much more soluble than O₂ that hypercapnia is rarely a problem in patients with pulmonary fibrosis. * However, it does occur in ventilation-perfusion inequality and when for any reason alveolar ventilation is inadequate in the various forms of pump failure.

Answer 533

* It is exacerbated with CO₂ production is increased. * For example, in febrile patients there is a 13% increase in CO₂ production for each 1°C rise in temperature * A high carbohydrate intake increases CO₂ production because of the increase in the respiratory quotient. * Normally, alveolar ventilation increases and the extra CO₂ is expired, but it accumulates when ventilation is compromised.

Answer 534

Hypocapnia is the result of hyperventilation. During voluntary hyperventilation, the arterial PCO₂ falls from 40 mmHg to as low as 15 mmHg while the alveolar PO₂ rises to 120-140 mmHg.

Answer 535

* The more chronic effects of hypocapnia are seen in neurotic patients who chronically hyperventilate. * Cerebral blood flow may be reduced 30% or more because of the direct constrictor effect of hypocapnia on the cerebral vessels. * The cerebral ischaemia causes light-headedness, dizziness and paraesthesias. * Hypocapnia also increases cardiac output. * It has a direct constrictor effect on many peripheral vessels, but it depresses the vasomotor center, so that the blood pressure is usually unchanged or only slightly elevated.

Answer 536

* The blood pH is increased to 7.5 or 7.6. * The **plasma HCO₃^- level is low** but **HCO₃^- reabsorption is decreased** because of the **inhibition of renal acid secretion by the low PCO₂.** * The plasma total calcium level does not change, but the **plasma Ca²⁺ level falls** and hypocapnic individuals develop carpopedal spasm, a positive Chvostek sign, and other signs of tetany.

Answer 537

* It is the formation of opaque vascular tissue in the eyes, which can lead to serious visual defects. * The retinal receptors mature from the center of the periphery of the retina, and they use considerable O₂. This causes the retina to become vascularised in an orderly manner. * Oxygen treatment before maturation is complete provides the needed O₂ to the photoreceptors, and consequently the normal vascular pattern fails to develop. * Evidence indicates that this condition can be prevented or ameliorated by treatment with vitamin E, which exerts an antioxidant effect.

Answer 538

* **Compliance** is developed due to the tendency for tissue to resume its original position after an applied force has been removed. * After an exapiration during quiet breathing, the lungs have a tendency to collapse and the chest wall has a tendency to expand.

Answer 539

* The interaction between the recoil of the lungs and the recoil of the chest can be measured through a spirometer that has a valve just beyond the mouthpiece. * The mouthpiece contains a pressure-measuring device. After the person inhales a given amount, the valve is shut, closing off the airway. * The respiratory muscles are then relaxed while the pressure in the airway is recorded. * The procedure is repeated after inhaling or activaly exhaling various volumes. * The curve of airway pressure obtained in this way, plotted against volume, is the **pressure-volume curve** of the total respiratory system.

Answer 540

* The pressure is 0 at a lung volume that corresponds to the volume of gas in the lungs at the FRC (relaxation volume). * This relaxation pressure is the sum of slightly negative pressure component from the chest wall (P_W) and a slightly positive pressure from the lungs (P_L) * The pressure in the total respiratory system (P_TR) is positive at greater volumes and negative at smaller volumes.

Answer 541

* **Compliance** of the lung and chest wall is measured as the slope of the P_TR curve, or , as a change in lung volume per unit change in airway pressure (ΔV/ΔP). * It is normally measured in the pressure range where the relaxation pressure curve is steepest, and normal values are ~0.2L/cm H₂O in a healthy adult man.

Answer 542

* Compliance depends on lung volume and thus can vary. * In an extreme example, an individual with only one lung has approximately half the ΔV for a given ΔP. * Compliance is also slightly greater when measured during deflation then when measured during inflation. Consequently, it is more informative to examine the whole pressure-volume curve.

Answer 543

* The curve is shifted downward and to the right (compliance is decreased) by pulmonary edema and interstitial pulmonary fibrosis. * The curve is shifted upward and to the left (compliance in increased) in emphysema

Answer 544

* Work is performed by the respiratory muscles in stretching the elastic tissues of the chest wall and lungs (65%), moving inelastic tissues (7%) and moving air through the respiratory passages (28%). * Because the dimensions of pressure x volume (g/cm² x cm³ = g x cm) has the same dimensions as work (force x distance ; g x cm), the work of breathing can be calculated from the pressure-volume curve. * The amount of elastic work required to inflate the whole respiratory system is less than the amount required to inflate the lungs alone because part of the work comes from elastic energy stored in the thorax.

Answer 545

* Because saline reduces the surface tension to nearly zero, the pressure-volume curve obtained with saline measures only the tissue elasticity * Whereas the curve obtained with air measures both tissue elasticity and surface tension.

Answer 546

* Differences are also obvious in the curves generated during inflation and deflation. This difference is termed **hysteresis**, and is notably not present in the saline generated curves. * The alveolar environment, and specifically the secreted factors that help reduce surface tension and keep alveoli from collapsing, contribute to hysteresis.

Answer 547

The low surface tension when the alveoli are small is due to the presence of **surfactant** in the fluid lining the alveoli.

Answer 548

DPPC, other lipids, and proteins

Answer 549

They would collapse in accordance with the law of Laplace. * In spherical structures like an alevolus, the distenging pressure (P) equals two times the tensions (T) divided by the radius (r) * P = 2T/r * If T is not reduced as r is reduced, the tension overcomes the distending pressure.

Answer 550

It has been calculated that if it were not present, the unopposed surface tension in the alveoli would produce a 20 mmHg force; such a force would greatly favour transudation of fluid from the blood into the alveoli.

Answer 551

* **SP-A** is a large glycoprotein and has a collagen-like domain within its structure. It regulates the feedback uptake of surfactant by the type II alveolar epithelial cells that secrete it. * **SP-B** and **SP-C** are smaller proteins, which are the key protein members of the monomolecular film of surfactant. * **SP-D** is a glycoprotein that plays an important role in the organisation of SP-B and SP-C into the surfactant layer. * Both **SP-A** and **SP-D** are members of the collectin family of proteins that are involved in the innate immunity in the conducting airway as well as in the alveoli.

Answer 552

* The walls of the pulmonary artery and its large branches are about 30% as thick as the wall of the aorta * The small arterial vessels, unlike the systemic arterioles, are endothelial tubes with relatively little muscle in their walls. * The walls of the post-capillary vessels also contain some smooth muscle. * The pulmonary capillaries are large, and there are multiple anastamoses, so that each alveolus sits in a capillary basket

Answer 553

1. There are anastomoses between the bronchial capillaries and the pulmonary capillaries and veins, and although some of the bronchial blood enters the bronchial veins, some enters the pulmonary capillaries and veins, bypassing the right ventricle. 2. Blood that flows from the coronary arteries into the chambers of the left side of the heart. Because of the small physiologic shunt created by those two exceptions, the blood in systemic arteries has a PO₂ about 2 mmHG lower than that of blood that has equilibrated with alveolar air, and the saturation of haemoglobin is 0.5% less.

Answer 554

The pressure gradient in the pulmonary system is about 7 mmHg, compared with a gradient of about 90 mmHg in the systemic circulation

Answer 555

* Pulmonary capillary pressure is about 10 mmHg, whereas the oncotic pressure is about 25 mmHg * An inward-directed pressure gradient of about 15 mmHg keeps the alveoli free of all but a thin film of fluid * When the capillary pressure is more than 25 mmHg, pulmonary congestion and oedema result.

Answer 556

The volume of blood in the pulmonary vessels at any one time is about 1L, of which less than 100mL is in the capillaries

Answer 557

The mean velocity of the blood in the root of the pulmonary artery is the same as that in the aorta (about 40cm/s). It falls off rapidly, then rises slightly again in the larger pulmonary veins.

Answer 558

It takes a red cell about 0.75 seconds to traverse the pulmonary capillaries at rest and 0.3 seconds or less during exercise

Answer 559

* In the upright position, the upper portions of the lungs are well above the level of the heart, and the bases are at or below it. * Consequently, in the upper part of the lungs, the blood flow is less, the alveoli are larger, and ventilation is less than at the base.

Answer 560

* The pressure in the capillaries at the top of the lungs is close to the atmospheric pressure in the alveoli. * Pulmonary arterial pressure is normally just sufficient to maintain perfusion, but if it is reduced or if alveolar pressure is increased, some of the capillaries collapse.

Answer 561

Under these circumstances, no gas exchange takes place in the affected aleoli and they become part of the **physiological dead space**.

Answer 562

* In the middle portions of the lungs, the pulmonary arterial and capillary pressure exceeds alveolar pressure, but the pressure in the pulmonary venules may be lower than alveolar pressure during normal expiration, so they are collapsed. * Thus, blood flow is determined by the pulmonary artery-alevolar pressure difference rather than the pulmonary artery-pulmonary vein difference. * Beyond the constriction, blood "falls" into the pulmonary veins, which are compliant and take whatever amount of blood the constriction lets flow into them. This has been called the **waterfall effect**.

Answer 563

In the lower portions of the lungs, alveolar pressure is lower than the pressure in all parts of the pulmonary circulation and blood flow is determined by the arterial-venous pressure difference.

Answer 564

* The ratio of pulmonary ventilation to pulmonary blood flow for the whole lung at rest is about 0.8 (4.2L/min ventilation / 5.5L/min blood flow). * Differences in this occur in various parts of the lung as a result of the effect of gravity.

Answer 565

* If the ventilation to an alveolus is reduced relative to its perfusion, the PO₂ in the alveolus falls because less O₂ is delivered to it and the PCO₂ rises because less CO₂ is expired. * Conversely, if perfusion is reduced relative to ventilation, the PCO₂ falls because less CO₂ is delivered and the PO₂ rises because less O₂ enters the blood

Answer 566

* Ventilation, as well as perfusion in the upright in position, declines in a linear fashion from the bases to the apices of the lungs. * However, the ventilation/perfusion ratios are high in the upper portions of the lungs

Answer 567

Constriction of the veins increases pulmonary capillary pressure and constriction of the pulmonary arteries increases the load on the right side of the heart.

Answer 568

* There is an extensive autonomic innervation of the pulmonary vessels, and stimulation of the cervical sympathetic ganglia reduces pulmonary blood flow by as much as 30%. * The vessels also respond to circulating humoral agents. Many of the dilator responses are endothelium-dependent and presumably operate via release of NO

Answer 569

Passive factors such as cardiac output and gravitational forces also have significant effects on pulmonary blood flow.

Answer 570

* With exercise, cardiac output increases and pulmonary arterial pressure rises. * More red cells move through the lungs without any reduction in the O₂ saturation of the Hb in them, and consequently, the total amount of O₂ delivered to the systemic circulation is increased. * Capillaries dilate, and previously underperfused capillaries are "recruited" to carry blood. * The net effect is a marked increase in pulmonary blood flow with few, if any, alterations in autonomic outflow to the pulmonary vessels.

Answer 571

* The O₂ deficiency apparently acts directly on vascular smooth area in the area to produce constriction, shunting blood away from the hypoxic area. * Accumulation of CO₂ leads to a drop in pH in the area, and a decline in pH also produces vasoconstriction in the lungs, as opposed to the vasodilation it produces in other tissues.

Answer 572

The alveolar PCO₂ in that area is lowered, and this leads to constriction of the bronchi supplying it, shifting ventilation away from the poorly perfused area.

Answer 573

It causes the pulmonary arterioles to constrict, with a resultant increase in pulmonary arterial pressure.

Answer 574

* They manufacture surfactant for local use. * They also contain a fibrinolytic system that lyses clots in the pulmonary vessels. * They release a variety of substances that enter the systemic arterial blood (prostaglandins, histamine, kallikrein) * The remove other substances from the systemic venous blood that reach them via the pulmonary artery (prostaglandins, bradykinin, serotonin, noradrenaline, acetylcholine)

Answer 575

Prostaglandins are removed from the circulation, but they are also synthesised in the lungs and released into the blood when lung tissue is stretched.

Answer 576

* The physiologically inactive decapeptide angiotenin I is converted to the pressor, aldosterone-stimulating octapeptide angiotensin II in the pulmonary circulation. * Large amounts of the angiotensin-converting enzyme responsible for this activation are located on the surface of the endothelial cells of the pulmonary capillaries.

Answer 577

The converting enzyme also inactivates bradykinin

Answer 578

Circulation time through the pulmonary capillaries is less than 1 second, yet 70% of the angiotensin I reaching the lungs is converted to angiotensin II in a single trip through the capillaries.

Answer 579

Removal of serotonin and noradrenaline reduces the amounts of these vasoactive substances reaching the systemic circulation

Answer 580

Myoglobin (an iron-containing pigment found in skeletal muscle) resembles Hb but binds 1 rather than 4 mol of O₂ per mole protein.

Answer 581

* The lack of cooperative binding is reflected in the myoglobin dissociation curve, a rectangular hyperbola rather than the sigmoid curve observed for haemoglobin * The leftward shift of the myoglobin O₂ binding curve when compared with HB demonstrates a higher affinity for O₂, and thus promoted a favourable transfer of O₂ from Hb in the blood.

Answer 582

* The steepness of the myoglobin curve also shows that O₂ is released only at low PO₂ values (eg, during exercise). * The myoglobin content is greatest in muscles specialised for sustained contraction. * The muscle blood supply is compressed during such contractions, and myoglobin can continue to provide O₂ under reduced blood flow and/or reduced PO₂ in the blood

Answer 583

The solubility of CO₂ in blood is about 20 times that of O₂; therefore, considerably more CO₂ than O₂ is present in simple solution at equal partial pressures.

Answer 584

* The CO₂ that diffuses into red blood cells is rapidly hydrated to H₂CO₃ because of the presence of carbonic anhydrase. * The H₂CO₃ dissociates to H⁺ and HCO₃^- and the H⁺ is buffered, primarily by haemoglobin, while the HCO₃^- enters the plasma

Answer 585

* Some of the CO₂ in the red cells reacts with the amino groups of Hb and other proteins, forming **carbamino compounds** * Because deoxyhaemoglobin binds more H⁺ than oxyhaemoglobin and forms carbamino compounds more readily, binding of O₂ to haemoglobin reduces its affinity for CO₂.

Answer 586

* The Haldane effect refers to the increased capacity of deoxygenated Hb to bind and carry CO₂. * Consequently, venous blood carries more CO₂ than arterial blood, CO₂ uptake is facilitated in the tissues and CO₂ release is facilitated in the lungs.

Answer 587

* The excess HCO₃^- leaves the red cells in exchange for Cl^-. * This process is mediated by **anion exchanger 1 (AE1)**, a major membrane protein in the red blood cell. * Because of this **chloride shift**, the Cl^- content of the red cells in venous blood is significantly greater than that in arterial blood. * The chloride shift occurs rapidly and is essentially complete within 1 second.

Answer 588

* Consequently, the red cells take up water and increase in size. * For this reason, plus the fact that a small amount of fluid in the arterial blood returns via the lymphatics rather than the veins, the haematocrit of venous blood is normally 3% greater than that of the arterial blood. * In the lungs, the Cl^- moves back out of the cells and they shrink.

Answer 589

**Plasma** 1) dissolved 2) formation of carbamino compounds with plasma protein 3) hydration, H⁺ buffered, HCO₃^- in plasma **In red blood cells** 1) dissolved 2) formation of carbamino-Hb 3) Hydration, H⁺ buffered, 70% of HCO₃^- enters the plasma 4) Cl^- shifts into cells; mOsm in cells increases

Answer 590

Cellular metabolism * The CO₂ formed by metabolism in the tissues is in large part hydrated to H₂CO₃, resulting in the large total H⁺ load * Most of the CO₂ is excreted in the lungs, and the small quantities of the remaining H⁺ are excreted by the kidneys

Answer 591

1. Proteins 2. Haemoglobin 3. The carbonic acid-bicarbonate system

Answer 592

They are effective buffers because both their free carboxyl and their free amino groups dissociate:

Answer 593

* It is provided by the dissociation of the imidazole groups of the histidine residues in Hb * In the pH 7.0-7.7 range, the free carboxyl and amino groups of Hb contribute relatively little to its buffering capacity. * However, the Hb contains 38 histidine residues, and this basis - plus the fact that Hb is present in large amounts - the Hb in blood has six times the buffering capacity of the plasma proteins.

Answer 594

* The imidazole groups of deoxyhaemoglobin (Hb) dissociate less than those of oxyhaemoglobin (HbO₂), making Hb a weaker acid and therefore a better buffer than HbO₂. * The titration curves for Hb and HbO₂ illustrate the differences in H⁺ buffering capacity.

Answer 595

The **carbonic acid-bicarbonate system**.

Answer 596

* Because the amount of dissolved CO₂ is controlled by respiration (it is an "open" system). * Additional control of the plasma concentration of HCO₃^- is provided by the kidneys

Answer 597

1. Extra H₂CO₃ that is formed is removed 2. The H⁺ rise stimulates respiration and therefore produces a drop in PCO₂, so that some additional H₂CO₃ is removed.

Answer 598

1) The reaction CO₂ + H₂O = H₂CO₃ proceeds slowly in either direction unless the enzyme **carbonic anhydrase** is present. There is no carbonic anhydrase in plasma, but there is an abundant supply in red blood cells, spatially confining and controlling the reaction 2) The presence of Hb in the blood increases the buffering of the system by binding free H⁺ produced by the hydration of CO₂ and allowing for the movement of the HCO₃^- into the plasma

Answer 599

* Any short-term rise in arterial PCO₂ (ie, above 40mmHg, due to hypoventilation results in **respiratory acidosis**. * CO₂ that is retained is in equilibrium with H₂CO₃, which in turn is in equilibrium with HCO₃^-. The effective rise in plasma HCO₃^- means that a new equilibrium is reached at a lower pH.

Answer 600

* Any short-term lowering of PCO₂ below what is needed for proper CO₂ exchange results in respiratory alkalosis. * The decreased CO₂ shifts the equilibrium of the carbonic acid-bicarbonate system to effectively lower H⁺ and increase pH.

Answer 601

**Metabolic acidosis** occurs when strong acids are added to blood. The H₂CO₃ that is formed is converted to H₂O and CO₂ and the CO₂ is rapidly excreted via the lungs. ## Footnote Note that in contrast to respiratory acidosis, metabolic acidosis does not include a change in PCO₂; the shift toward metabolic acidosis occurs along an isobar line

Answer 602

When the free H⁺ level falls as result of addition on alkali, or more commonly, the removal of large amounts of acid (following vomiting), **metabolic alkalosis** results.

Answer 603

**Metabolic acidosis** - Ventilation is increased, resulting in a decrease of PCO₂ and a subsequent increase in pH toward normal **Metabolic alkalosis** - Ventilation is decreased, PCO₂ is increased, and a subsequent decrease in pH occurs

Answer 604

* The kidney response to acidosis by actively secreting fixed acids while retaining filtered HCO₃^-. * In contrast, the kidney responds to alkalosis by decreasing H⁺ secretion and by decreasing retention of filtered HCO₃^-.

Answer 605

* This can produce H⁺ and HCO₃^- from CO₂. * In response to acidosis, these cells secrete H⁺ into the tubular fluid in exchange for Na⁺ while the HCO₃^- is actively reabsorbed into the peritubular capillary; for each H⁺ secreted, one Na⁺ and one HCO₃^- are added to the blood. * In response to alkalosis, the kidney decreases H⁺ secretion and depresses HCO₃^- reabsorption

Answer 606

* Spontaneous respiration is produced by rhythmic discharge of motor neurons that innervate the respiratory muscles. * This discharge is totally dependent on nerve impulses from the brain; breathing stops if the spinal cord is transected above the origin of the phrenic nerves. * The rhythmic discharges from the brain that produce spontaneous respiration are regulated by alterations in arterial PO₂, PCO₂ and H⁺ concentration, and this chemical control of breathing is supplemented by a number of non-chemical influences.

Answer 607

One is responsible for voluntary control and the other for automatic control.

Answer 608

* The **voluntary system** is located in the **cerebral cortex** and sends impulses to the respiratory motor neurons via the **corticospinal tracts**. * The **automatic system** is driven by a group of **pacemaker cells in the medulla**. Impulses from these cells activate motor neurons in the cervical and thoracic spinal cord that innervate inspiratory muscles. * Those in the **cervical cord** activate the diaphragm via the **phrenic nerves**, and those in the **thoracic spinal cord** activate the **external intercostal muscles**. However, the impulses also reach the innervation of the internal intercostal muscles and other expiratory muscles.

Answer 609

* The motor neurons to the expiratory muscles are inhibited when those supplying the inspiratory muscles are active, and vice versa. * Although spinal reflexes contribute to this reciprocal innervation, it is due primary to activity in descending pathways. * Impulses in these descending pathways excite agonists and inhibit antagonists.

Answer 610

A small amount of activity in phrenic axons for a short period after inspiration. The function of this postinspiratory output appears to be to brake the lung's elastic recoil and make respiration smooth.

Answer 611

* They are located in the medulla * Rhythmic respiration is initiated by a small group of synaptically coupled pacemaker cells in the **pre-Bötzinger complex** on either side of the medulla between the nucleus ambiguous and the lateral reticular nucleus.

Answer 612

These neurons discharge rhythmically and they produce rhythmic discharges in phrenic motor neurons that are abolished by sections between the pre-Bötzinger complex and these motor neurons. They also contact the hypoglossal nuclei, and the tongue is involved in the regulation of airway resistance

Answer 613

* There are NK1 receptors and μ-opioid receptors on the neurons in the pre-Bötzinger complex that discharge rhythmically. * Substance P simulates and opioids inhibit respiration.

Answer 614

* Lesions of these neurons do not abolish respiratory activity * They apparently project to the pre-Bötzinger complex pacemaker neurons.

Answer 615

* An area known as the **pneumotaxic centre** in the **medial parabrachial** and **Kölliker-Fuse nuclei** of the **dorsolateral pons** contain neurons active during inspiration and neurons active during expiration. * It may play a role in switching between inspiration and expiration * When this area is damaged, respiration becomes slowed and tidal volume greater, and when the vagi are also cut in anaesthetised animals, there are prolonged inspiratory spasms that resemble breath holding.

Answer 616

* Stretching of the lungs during inspiration initiates impulses in afferent pulmonary vagal fibres. * These impulses inhibit inspiratory discharge. * Vagal feedback activity does not alter the rate of rise of the neural activity in respiratory motor neurons

Answer 617

* The rate and the depth of breathing are increased. * The depth of respiration is increased because the lungs are stretched to a greater degree before the amount of vagal and pneumotaxic centre inhibitory activity is sufficient to overcome the more intense inspiratory neuron discharge. * The respiratory rate is increased because the after-discharge in the vagal and possibly the pneumotaxic afferents to the medulla is rapidly overcome

Answer 618

* A rise in the PCO₂ or H⁺ concentration of arterial blood or a drop in its PO₂ increases the level of respiratory neuron activity in the medulla, and changes in the opposite direction have a slight inhibitory effect. * The effect of variations in blood chemistry on ventilation are mediated via respiratory **chemoreceptors** - the carotid and aortic bodies and collections of cells in the medulla. * They initiate impulses that stimulate the respiratory centre.

Answer 619

* The respiratory minute volume is proportional to the metabolic rate, but the link between metabolism and ventilation is CO₂ not O₂. * The receptors in the carotid and aortic bodies are stimulated by a rise in the PCO₂ or H⁺ concentration of arterial blood or a decline in its PO₂.

Answer 620

* The response to a drop in PO₂ is abolished; the predominant effect of hypoxia after denervation of the carotid bodies is a direct depression of the respiratory centre. * The response to changes in arterial blood H⁺ concentration in the pH 7.3-7.5 range is also abolished. * The response to changes in arterial PCO₂, on the other hand, is affected only slightly, it is reduced no more than 30-35%.

Answer 621

* **Type I or glomus cells** - are closely associated with cuplike endings of the afferent nerves. They resemble adrenal chromaffin cells and have dense-core granules containing catecholamines that are released upon exposure to hypoxia and cyanide. The cells are excited by hypoxia, and the principal transmitter appears to be dopamine, which excites the nerve endings by way of D₂ receptors. * The **type II cells** are glia-like and each surrounds four-to-six type I cells. Their function is not fully defined

Answer 622

* Outside the capsule of each body, the nerve fibres acquire a myelin sheath; however, they are only 2-5μm in diameter and conduct at the relatively low rate of 7-12m/s. * Afferents from the carotid bodies ascend to the medulla via the carotid sinus and glossopharyngeal nerves * Afferents from the aortic bodies ascend in the vagi.

Answer 623

Yes, there is a graded increase in impulse traffic in the afferent fibres from the carotid and aortic bodies as the PO₂ of the perfusing blood is lowered or the PCO₂ is raised.

Answer 624

* They have O₂ sensitive K⁺ channels, whose conductance is reduced in proportion to the degree of hypoxia to which they are exposed. * This reduces the K⁺ efflux, depolarising the cell and causing Ca²⁺ influx, primarily via L-type Ca²⁺. * The Ca²⁺ influx triggers action potentials and transmitter release, with consequent excitation of the afferent nerve endings.

Answer 625

* The smooth muscle of pulmonary arteries contains similar O₂ sensitive K⁺ channels to the glomus cells, which mediate the vasoconstriction caused by hypoxia. * This is in contrast to the systemic arteries, which contain ATP-dependent K⁺ channels that permit more K⁺ efflux with hypoxia and consequently cause vasodilation instead of vasoconstriction.

Answer 626

The blood flow in each 2mg carotid body is about 0.04mL/min, or 2000mL/100g of tissue/min compared with a blood flow of 54mL or 420mL per 100g/min in the brain and kidneys respectively.

Answer 627

* Because the blood flow per unit of tissue is so enormous, the O₂ need of the cells can be met largely by dissolved O₂ alone. * Therefore, the receptors are not stimulated in conditions such as anaemia or CO poisoning, in which the amount of dissolved O₂ in the blood reaching the receptors is generally normal, even though the combined O₂ in the blood is markedly decreased.

Answer 628

* The receptors are stimulated when the arterial PO₂ is low or when, because of vascular stasis, the amount of O₂ delivered to the receptors per unit time is decreased. * Powerful stimulation is also produced by cyanide, which prevents O₂ utilisation at the tissue level. * In sufficient doses, nicotine and lobelia active the chemoreceptors. * The infusion of K⁺ increases the discharge rate in chemoreceptor afferents, and because the plasma K⁺ level is increased during exercise, the increase may contribute to exercise-induced hyperpnea.

Answer 629

* They are separate from the dorsal and ventral respiratory neurons and are located on the ventral surface of the medulla. * The chemoreceptors monitor the H⁺ concentration of CSF. CO₂ readily penetrates membranes, including the blood-brain barrier, whereas H⁺ and HCO₃^- penetrate slowly. * The CO₂ that enters the brain and CSF is promptly hydrated. The H₂CO₃ dissociates, so that the local H⁺ concentration rises. * The H⁺ concentration in brain interstitial fluid parallels the arterial PCO₂.

Answer 630

The effects of CO₂ on respiration are mainly due to its movement into the CSF and brain interstitial fluid, where it increases the H⁺ concentration and stimulates receptors sensitive to H⁺

Answer 631

* In metabolic acidosis there is pronounced respiratory stimulation (Kussmaul breathing). The hyperventilation decreases alveolar PCO₂ and thus produces a compensatory fall in blood H⁺ concentration. * In metabolic alkalosis, ventilation is depressed and the arterial PCO₂ rises, raising the H⁺ concentration toward normal.

Answer 632

* The arterial PCO₂ is normally maintained at 40mmHg. * When arterial PCO₂ rises as a result of increased tissue metabolism, ventilation is stimulated and the rate of pulmonary excretion of CO₂ increases until the arterial PCO₂ falls to normal, shutting off the stimulus. * The operation of this feedback mechanism keeps CO₂ excretion and production in balance

Answer 633

* When a gas mixture containing CO₂ is inhaled, the alveolar PCO₂ rises, elevating the arterial PCO₂ and stimulating ventilation as soon as the blood containing more CO₂ reaches the medulla. * CO₂ elimination is increased and the alveolar PCO₂ drops toward normal. * However, the PCO₂ does not drop to normal, and a new equilibrium is reached at which the alveolar PCO₂ is slightly elevated and the hyperventilation persists as long as CO₂ is inhaled. * The essentially linear relationship between respiratory minute volume and the alveolar PCO₂ is shown in this graph.

Answer 634

* When the PCO₂ of the inspired gas is close to the alveolar PCO₂, elimination of CO₂ becomes difficult. * When the CO₂ content of the inspired gas is more than 7%, the alveolar and arterial PCO₂ begin to rise abruptly despite hyperventilation. * The resultant accumulation of CO₂ in the body (hypercapnia) depressed the CNS, including the respiratory center, and produces headache, confusion, and eventually coma (CO₂ narcosis)

Answer 635

* When the O₂ content of the inspired air is decreased, respiratory minute volume is increased. * The stimulation is slight when the PO₂ of the inspired air is more than 60mmHg, and marked stimulation occurs only at lower PO₂ values. * However, any decline in arterial PO₂ below 100mmHg produces increased discharge in the nerves from the carotid and aortic chemoreceptors

Answer 636

1. Because Hb is a weaker acid than HbO₂, there is a slight decrease in the H⁺ concentration of arterial blood when the arterial PO₂ falls and Hb becomes less saturated with O₂. The fall in H⁺ concentration tends to inhibit respiration. 2. Any increase in ventilation that does occur lowers the alveolar PCO₂, and this also tends to inhibit respiration. Therefore, the stimulatory effects of hypoxia on ventilation are not clearly manifest until they become strong enough to override the counterbalancing inhibitory effects of a decline in arterial H⁺ concentration and PCO₂

Answer 637

* When the CO₂ response is tested at different fixed PO₂ values, the slope of the response curve changes, with the slope increased when alveolar PO₂ is decreased. * In other worse, hypoxia makes the individual more sensitive to an increase in arterial PCO₂. * However, the alveolar PCO₂ level at which the curves in the graph intersect is unaffected. * In the normal individual, this threshold value is just below the normal alveolar PCO₂, indicating that normally there is a very slight but definite "CO₂ drive" of the respiratory area.

Answer 638

* When the alveolar PCO₂ is stabilised at a level 2-3 mmHg above normal, there is an inverse relationship between ventilation and the alveolar PO₂ even in the 90-110 mmHg range * But when the alveolar PCO₂ is fixed at lower than normal values, there is no stimulation of ventilation by hypoxia until the alveolar PO₂ falls below 60 mmHg

Answer 639

* The stimulatory effects of H⁺ and CO₂ on respiration appear to be additive * In metabolic acidosis, the same amount of respiratory stimulus is produced by lower arterial PCO₂ levels.

Answer 640

* The point at which breathing can no longer by voluntarily inhibited is called the **breaking point**. * Breaking is due to the rise in arterial PCO₂ and the fall in PO₂ .

Answer 641

* Breathing 100% oxygen before breath holding raises alveolar PO₂ initially, so that the breaking point is delayed. * Same as above with hyperventilating room air, because CO₂ is blown off and arterial PCO₂ is lower at the start. * Psychological factors also play a role, people can hold their breath for longer if they're told they're good at it.

Answer 642

Myelinated and unmyelinated (C type) vagal fibers.

Answer 643

* The receptors innervated by myelinated fibers are commonly divided into **slowly adapting receptors** and **rapidly adapting receptors** on the basis of whether sustained stimulation leads to prolonged or transient discharge in their afferent nerve fibers. * The other groups of receptors consists of the endings of C fibers, and they are divided into pulmonary and bronchial subgroups based on their location

Answer 644

* The shortening of inspiration produced by vagal afferent activity is mediated by slowly adapting receptors, as are the **Hering-Breuer reflexes**. * The Hering-Breuer inflation reflex is an increase in the duration of expiration produced by steady lung inflation * The Hering-Breuer deflation reflex is a decrease in the duration of expiration produced by marked deflation of the lung.

Answer 645

* Because the rapidly adapting receptors are stimulated by chemicals such as histamine, they have been called **irritant receptors**. * Activation of rapidly adapting receptors in the trachea causes coughing, bronchoconstriction, and mucus secretion, and activation of rapidly adapting receptors in the lung may produce hyperpnea.

Answer 646

* Because the C fiber endings are close to pulmonary vessels, they have been called J (juxtacapillary) receptors. * They are stimulated by hyperinflation of the lung, but they respond well to IV or intracardiac administration of chemical such as capsaicin.

Answer 647

* The reflex response that is produced is apnea followed by rapid breathing, bradycardia, and hypotension(**pulmonary chemoreflex**). * A similar response is produced by receptors in the heart (**Bezold-Jarisch reflex** or the **coronary chemoreflex**). * The physiological role of this reflex is uncertain, but it probably occurs in pathological states such as pulmonary congestion or embolisation, in which it is produced by endogenously released substances

Answer 648

* Coughing begins with a deep inspiration followed by forced expiration against a closed glottis. * This increases the intrapleural pressure to 100mmHg or more. * The glottis is then suddenly opened, producing an explosive outflow of air at velocities up to 965km (600 miles) per hour. * Sneezing is a similar expiratory effort with a continuously open glottis.

Answer 649

* Inhibition of respiration and closure of the glottis during vomiting, swallowing, and sneezing prevents the aspiration of food or vomit into the trachea * In the case of vomiting, it also fixes the chest so that contraction of the abdominal muscles increases the intra-abdominal pressure.

Answer 650

* It is a spasmodic contraction of the diaphragm and other inspiratory muscles that produces an inspiration during which the glottis suddenly closes. * The glottic closure is responsible for the characteristic sensation and sound.

Answer 651

* Afferent fibers from baroreceptors in the carotid sinuses, aortic arch, atria, and ventricles relay to the respiratory neurons, as well as the vasomotor and cardioinhibitory neurons in the medulla. * Impulses in them inhibit respiration, but the inhibitory effect is slight and of little physiological importance. * The hyperventilation in shock is due to chemoreceptor stimulation causes by acidosis and hypoxia secondary to local stagnation of blood flow, and is not baroreceptor-mediated.

Answer 652

* Respiration is less rigorously controlled during sleep than in the waking state, and brief periods of apnea occur in normal sleeping adults. * Changes in the ventilatory response to hypoxia vary * If the PCO₂ falls during the waking state, various stimuli from proprioceptors and the environment maintain respiration, but during sleep, these stimuli are decreased and a decrease in PCO₂ can cause apnea. * During REM sleep, breathing is irregular and the CO₂ response is highly variable.

Answer 653

* In asphyxia produced by occlusion of the airway, acute hypercapnia and hypoxia develop together. * Stimulation of respiration is pronounced, with violent respiratory effects. * Blood pressure and HR rise sharply, catecholamine secretion is increased, and blood pH drops * Eventually, the respiratory efforts cease, the blood pressure falls, and the heart slows. * In artificial respiration is not started, cardiac arrest occurs in 4-5 minutes.

Answer 654

* Drowning is asphyxia caused by immersion, usually in water. * In about 10% of drownings, the first gasp of water after losing the struggle not to breathe triggers laryngospasm, and death results from the asphyxia without any water in the lungs. * In the remaining cases, the glottis muscles eventually relax and fluid enters the lungs

Answer 655

* Fresh water is rapidly absorbed, diluting the plasma and causing intravascular haemolysis. * Ocean water is markedly hypertonic and draws fluid from the vascular system into the lungs, decreasing the plasma volume. * The immediate goal in the treatment of drowning is obviously resuscitation, but long-term treatment must also take into account the circulatory effects of the water in the lungs.

Answer 656

* When a normal individual hyperventilates for 2-3 minutes, then stops and permits respiration to continue without exerting any voluntary control over it, a period of apnea occurs. * This is followed by a few shallow breaths and then by another period of apnea, followed again by a few breaths (**periodic breathing**).

Answer 657

* The apnea apparently is due to a lack of CO₂ because it does not occur following hyperventilation with gas mixtures containing 5% CO₂ . * During the apnea, the alveolar PO₂ falls and PCO₂ rises. * Breathing resumes because of hypoxic stimulation of the carotid and aortic chemoreceptors before the CO₂ level has returned to normal. * A few breaths eliminate the hypoxic stimulus, and breathing stops until the alveolar PO₂ falls again. * Gradually, however, the PCO₂ returns to normal, and normal breathing resumes.

Answer 658

* Circulatory changes increase muscle blood flow while maintaining adequate circulation in the rest of the body. * There is an increase in the extraction of O₂ from the blood in exercising muscles and an increase in ventilation. * This provides extra O₂, eliminates some of the heat, and excretes extra CO₂.

Answer 659

During exercise, the amount of O₂ entering the blood in the lungs is increased because the amount of O₂ added to each unit of blood and the pulmonary blood flow per minute are increased.

Answer 660

The PO₂ of blood flowing into the pulmonary capillaries falls from 40 to 25 mmHg or less, so that the alveolar capillary PO₂ gradient is increased and more O₂ enters the blood

Answer 661

* Blood flow per minute is increased from 5.5L/minute to as much as 20-35L/minute. * The total amount of O₂ entering the blood therefore increases from 250mL/minute at rest to values as high as 4000mL/minute. * The amount of CO₂ removed from each unit of blood is increased, and CO₂ excretion increases from 200mL/minute to as much as 8000mL/minute.

Answer 662

* The increase in O₂ uptake is proportional to work load, up to a maximum. * Above this maximum, O₂ consumption levels off and the blood lactate level continues to rise. * The lactate comes from muscles in which aerobic resynthesis of energy stores cannot keep pace with their utilisation, and an **oxygen debt is being incurred**

Answer 663

* Ventilation increases abruptly with the onset of exercise which is followed after a brief pause by a further, more gradual increase. * With moderate exercise, the increase is due mostly to an increase in the depth of respiration. This is accompanied by an increase in the resp rate when the exercise is more strenuous. * Ventilation abruptly decreases when exercise ceases, which is followed after a brief pause followed by a more gradual decline to preexercise values.

Answer 664

* The abrupt increase at the start of exercise is presumably due to psychic stimuli and afferent impulses from proprioceptors in muscles, tendons, and joints. * The more gradual increase is presumably humeral, even though arterial pH, PCO₂ and PO₂ remain constant during moderate exercise.

Answer 665

The mechanisms responsible are still up for debate. It could be: * the increase in body temperature * exercise increases the plasma K⁺ level, and this increase may stimulate the peripheral chemoreceptors. * the sensitivity of the neurons controlling the response to CO₂ is increased * the respiratory fluctuations in arterial PCO₂ increase so that, even though the mean arterial PCO₂ does not rise, it is CO₂ that is responsible for the increase in ventilation

Answer 666

Buffering the increased amounts of lactic acid that are produced liberates more CO₂, and this further increases ventilation.

Answer 667

* With increased production of acid, the increases in ventilation and CO₂ remain proportional, so alveolar and arterial CO₂ change relatively little (**isocapnic buffering**). * Because of the hyperventilation, the alveolar PO₂ increases. * With further accumulation of lactic acid, the increase in ventilation outstrips CO₂ production and alveolar PCO₂ falls, as does PCO₂. * The decline in arterial PCO₂ provides respiratory compensation for the metabolic acidosis produced by the additional lactic acid. * The additional increase in ventilation produced by the acidosis depends on the carotid bodies and does not occur if they are removed.

Answer 668

* The respiratory rate after exercise does not reach basal levels until the O₂ debt is repaid. This may take as long as 90 minutes. * The stimulus to ventilation after exercise is not the arterial PCO₂, which is normal or low, or the arterial PO₂, which is normal or high, but the elevated arterial H⁺ concentration due to the lactic acidaemia. * The magnitude of the O₂ debt is the amount by which O₂ consumption exceeds basal consumption from the end of exertion until the O₂ consumption has returned to pre exercise basal levels.

Answer 669

* The O₂ concentration in muscle myoglobin rises slightly. ATP and phosphorylcreatine are resynthesised, and lactic acid is removed. * 80% of the lactic acid is converted to glycogen and 20% is metabolised to CO₂ and H₂O

Answer 670

* Maximum uptake during exercise is limited by the maximum rate at which O₂ is transported to the mitochondria in the exercising muscle. * However, this limitation is not normally due to deficient O₂ uptake in the lungs, and Hb in arterial blood is saturated even during the most severe exercise.

Answer 671

* During exercise, the contracting muscles use more O₂, and the tissue PO₂ and the PO₂ in venous blood from exercising muscle fall nearly to zero. * More O₂ diffuses from the blood and the blood PO₂ of the blood in the muscles drops, and more O₂ is removed from Hb. * Because the capillary bed of contracting muscle is dilated and many previously close capillaries are open, the mean distance from the blood to the tissue cells is greatly decreased.

Answer 672

* The oxygen-Hb dissociation curve is steep in the PO₂ range below 60 mmHg (during exercise) and a relatively large amount of O₂ is supplied for each drop of 1mmHg in PO₂. * Additional O₂ is supplied because, as a result of the accumulation of the CO₂ and the rise in temperature in active tissues - and perhaps the rise in RBC 2,3-DPG) - the dissociation curve shifts to the right. * The net effect is a 3-fold increase in O₂ extraction from each unit of blood. * Because this increase is accompanied by a 30-fold or greater increase in blood flow, it permits the metabolic rate of muscle to rise as much as 100-fold during exercise.

Answer 673

It is produced in part by bombardment of the brain by neural impulses from muscles, and the decline in blood pH produced by lactic acidosis also makes one feel tired, as does the rise in body temperature, dyspnea and perhaps the uncomfortable sensations produced by activation of the J receptors in the lungs

Answer 674

* Each individual renal tubule and its glomerulus is a unit (nephron) * The size of the kidneys between species varies, as does the number of nephrons they contain * Each human kidney has approximately 1 million nephrons

Answer 675

The glomerulus, which is about 200μm in diameter, is formed by the invagination of a tuft of capillaries into the dilated, blind end of the nephron (**Bowman's capsule**)

Answer 676

The capillaries in glomerulus are supplied by an **afferent arteriole** and drained by the **efferent arteriole**, and it is from the glomerulus that the filtrate is formed.

Answer 677

The diameter of the afferent arteriole is larger than the efferent arteriole

Answer 678

* The capillary endothelium and the specialised endothelium of the capsule. * The endothelium of the glomerular capillaries is fenestrated with pores that are 70-90nm in diameter. It is completely surrounded by the glomerular basement membrane along with specialised cells called **Podocytes**. * Podocytes have numerous pseudopodia that interdigitate to form **filtration slits** along the capillary wall. The slits are approximately 25nm wide, and each is closed by a thin membrane. * The glomerular basement membrane, the basal lamina, does not contain visible gaps or pores.

Answer 679

* They are similar to cells called **pericytes**, which are found in the walls of capillaries elsewhere in the body. * Mesangial cells are especially common between two neighbouring capillaries, and in these locations the basal membrane forms a sheath shared by both capillaries. * The mesangial cells are contractile and play a role in the regulation of glomerular filtration * Mesangial cells secrete the extracellular matrix, take up immune complexes, and are involved in the progression of glomerular disease

Answer 680

* Functionally, the glomerular membrane permits the free passage of neutral substances up to 4nm in diameter and almost totally excludes those with diameters greater than 8nm. * However, the charge on molecules as well as their diameters affects their passage into Bowman's capsule. * The total area of glomerular endothelium across which filtration occurs in humans is about 0.8m²

Answer 681

* The human **proximal convoluted tubule** is about 15mm long and 55μm in diameter. * Its wall is made up of a single layer of cells that interdigitate with one another and are united by apical tight junctions. * Between the cells are extensions of the extracellular space called the **lateral intercellular spaces**. * The luminal edges of the cells have a striated **brush border** due to the presence of many microvilli.

Answer 682

* The descending portion of the loop and the proximal portion of the ascending limb are made up of thin, permeable cells * On the other hand the thick portion of the ascending limb is made up of thick cells containing many mitochondria.

Answer 683

* The nephrons with glomeruli in the outer portions of the renal cortex have short loops of Henle (**cortical nephrons**) * Whereas those with glomeruli in the juxtamedullary region of the cortex (**juxtamedully nephrons**) have long loops extending down into the medullary pyramids. * In humans, only 15% of the nephrons have long loops

Answer 684

* Specialised cells at the end form the **macula densa**, which is close to the efferent and particularly afferent arteriole * The macula, the neighbouring **lacis cells**, and the renin-secreting **granular cells** in the afferent arteriole form the **juxtaglomerular apparatus**.

Answer 685

* It is about 5mm long * Its epithelium is lower than that of the proximal tubule, although a few microvilli are present, there is no distinct brush border

Answer 686

They are about 20mm long and pass through the renal cortex and medulla to empty into the pelvis of the kidney at the apex of the medullary pyramid .

Answer 687

* The epithelium of the collecting ducts is made up to **principal cells (P cells)** and **intercalated cells (I cells)**. * The P cells, which predominate are relatively tall and have few organelles. They are involved in Na⁺ reabsorption and vasopressin-stimulated water reabsorption * The I cells, which are present in smaller numbers are also found in the distal tubules, have more microvilli, cytoplasmic vesicles, and mitochondria. They are concerned with acid secretion, and HCO₃^- transport.

Answer 688

It ranges from 45 to 65mm

Answer 689

* These cells are called **renal medullary interstitial cells (RMICs)** and are specialised fibroblast-like cells * They contain lipid droplets and are a major site of COX-2 and prostaglandin synthase expression * PGE₂ is the major prostanoid synthesised in the kidney and is an important paracrine regulator of salt and water homeostasis. * PGEx₂ is secreted by the RMICs by the macula densa, and by cells in the collecting ducts; prostacyclin (PGI₂) and other prostaglandins are secreted by the arterioles and glomeruli

Answer 690

* The **afferent arterioles** are short, straight branches of the interlobular arteries * Each divides into multiple capillary branches to form the tuft of vessels in the glomerulus * The capillaries coalesce to form the **efferent arteriole**, which in turn breaks up into capillaries that supply the tubules (**peritubular capillaries**) before draining into the interlobular veins

Answer 691

* The arterial segments between the glomeruli and tubules are technically a portal system, and the glomerular capillaries are the only capillaries in the body that drain into arterioles. * However, there is relatively little smooth muscles in the efferent arterioles

Answer 692

* The capillaries draining the tubules of the cortical nephrons form a peritubular network, where the efferent arterioles from the juxtamedullary glomeruli drain not only into the peritubular network, but also into vessels that form the hairpin loops (the **vasa recta**) * These loops dip into the medially pyramids alongside the loops of Henle. * The descending vasa recta have a nonfenestrated endothelium that contains a facilitated transporter for urea, and the ascending vasa recta have a fenestrated endothelium, consistent with their function in conserving solutes

Answer 693

Thus, the tubule of each nephron does not necessarily receive blood solely from the efferent arteriole of the same nephron

Answer 694

* The total surface of the renal capillaries is approximately equal to the surface area of the tubules, both being about 12m². * The volume of blood in the renal capillaries at any given time is about 30-40mL

Answer 695

* The kidneys have an abundant lymphatic supply that drains via the thoracic ducts into the venous circulation in the thorax

Answer 696

* The renal capsule in thin but tough * If the kidney becomes oedematous, the capsule limits the swelling, and the tissue pressure (**renal interstitial pressure**) rises. * This decreases the GFR and is claimed to enhance and prolong anuria in AKI.

Answer 697

* They contain many postganglionic sympathetic efferent fibers and a few afferent fibres. * There also appears to be a cholinergic innervation via the vagus nerve, but its function is uncertain * The sympathetic preganglionic innervation comes primarily from the lower thoracic and upper lumbar segments of the spinal cord, * The cell bodies of the postganglionic neurons are in the sympathetic ganglion chain, in the superior mesenteric ganglion, and along the renal artery.

Answer 698

* The sympathetic fibers are distributed primarily to the afferent and efferent arterioles, the proximal and distal tubules, an the juxtaglomerular apparatus * In addition, there is a dense **noradrenergic** innervation of the thick ascending loop limb of the loop of Henle

Answer 699

Nociceptive afferents that mediate pain in kidney disease parallel the sympathetic efferents and enter the spinal cord in the thoracic and upper lumbar dorsal roots

Answer 700

* Other renal afferents presumably mediate a **renorenal reflex** by which an increase in ureteral pressure in one kidney leads to a decrease in efferent nerve activity to the contralateral kidney

Answer 701

In a resulting adults, the kidneys receive 1.2-1.3L of blood per minute, or just under 25% of the cardiac output.

Answer 702

* It can be measured with electromagnetic or other types of flow meters, or it can be determined by applying the Fick principle to the kidney * Ficks method is by measuring the amount of a given substance taken up per unit of time and dividing this value by the arteriovenous different for the substance across the kidney.

Answer 703

* Because the kidney filters plasma, the **renal plasma flow** (RPF) equals the amount of a substance excreted per unit of time divided by the renal arteriovenous difference as long as the amount in the red cells in unaltered during passage through the kidney * Any excreted substance can be used if its concentration in arterial and renal venous plasma can be measured and if it is not metabolised, stored or produced by the kidney and does not itself affect blood flow

Answer 704

* GFR is the amount of plasma ultra filtrate formed each minute and can be measured in intact experimental animals and humans by measuring the plasma level of a substance and the amount of that substance that is excreted. * A substance to be used to measure GFR must be freely filtered through the glomeruli and must be neither secreted not reabsorbed by the tubules

Answer 705

Inulin, a polymer of fructose with a molecular weight of 5200, is used to measure GFR

Answer 706

* Renal plasma clearance is the **volume of plasma** from which a substance is completely removed by the kidney in a given amount of time (usually minutes) * The amount of that substance that appears in the urine per unit of time is the result of the renal filtering of a certain number of mLs of plasma that contained this amount. * GFR and clearance are measures in mL/min.

Answer 707

* If a substance is designated by the letter X, the GFR is equal to the concentration of X in the urine (U_X) times the urine flow per unit of time (V) divided by the arterial plasma of X (P_X) or V/P_X * This value is called the clearance of X (CX)

Answer 708

* A loading dose of inulin is administered IV, following a sustaining infusion to keep the arterial plasma level constant. * After the inulin has equilibrated with body fluids, an accurately timed urine specimen is collected and a plasma sample obtained halfway through the collection. * Plasma and urinary inulin concentrations are determined and the clearance is calculated.

Answer 709

* Some creatinine is secreted by the tubules, thus the clearance of creatinine will be slightly higher than inulin * In spite of this, the clearance of endogenous creatinine is a reasonable estimate of GFR as the values agree quite well with the GFR values measured with inulin.

Answer 710

* Glucose - 0ml/min * Sodium - 0.9ml/min * Chloride - 1.3ml/min * Potassium - 12ml/min * Phosphate - 25ml/min * Urea - 75ml/min * Inulin - 125ml/min * Creatinine - 140ml/min * PAH - 560ml/min

Answer 711

* The GFR in a healthy adult of average size is approximately 125ml/min * Its magnitude correlates fairly well with surface area, but values in women are 10% lower than those in men even after correction for surface area.

Answer 712

No * A rate of 125ml/min is 7.5L/h or 180L/day, whereas the normal urine volume is about 1L/day * Thus, 99% or more of the filtrate is normally reabsorbed * At the rate of 125ml/min, in 1 day the kidneys filter an amount of fluid equal to four times the total body water, 15 times the ECF volume and about 60 times the plasma volume

Answer 713

* The size of the capillary bed, the permeability of the capillaries and the hydrostatic and osmotic pressure gradients across the capillary wall. GFR = K_f [(P_GC - P_T) - (π_GC - π_T)] K_f = the glomerular ultrafiltration coefficient, is the product of the glomerular capillary wall hydraulic conductivity (ie, its permeability) and the effective filtration surface area P_GC = mean hydrostatic pressure in the glomerular capillaries P_T = mean hydrostatic pressure in the tubule (Bowman's space) π_GC = oncotic pressure in the glomerular capillaries π_T = oncotic pressure of the filtrate in the tubule (Bowman's space)

Answer 714

* Neutral substances with effective molecular diameters of less than 4nm are freely filtered, and the filtration of neutral substances with diameters or more than 8nm approaches zero. * Between these values, filtration is inversely proportional to diameter.

Answer 715

* The negative charges repel negatively charged substances in blood, with the result that filtration of anionic substances 4nm in diameter is less that half of that of neutral substances of the same size * This explains why albumin, with an effective molecular diameter of 7nm, normally has a glomerular concentration only 0.2% of its plasma concentration rather, because it is negatively charged * Conversely, filtration of cationic substances is greater than that of neutral substances

Answer 716

* The amount of protein in the urine is normally less that 100mg/day, and most of this is not filtered but comes from shed tubular cells * The presence of significant amounts of albumin in the urine is called **albuminuria** * In nephritis, the negative charges in the glomerular wall are dissipated, and albuminuria can occur for this reason without an increase in the size of the "pores" in the membrane.

Answer 717

**Contraction** Endothelins **Angiotensin II** Vasopressin Noradrenaline Platelet-activating factor Platelet-derived growth factor Thromboxane A₂ PGF₂ Leukotrienes C₄ and D₄ Histamine **Relaxation** ANP Dopamine PGE₂ cAMP

Answer 718

* K_f can be altered by the mesangial cells, with contraction of these cells producing a decrease in K_f that is largely due to a reduction in the area available for filtration. * Contraction of points where the capillary loops bifurcate probably shifts flow away from some of the loops, and elsewhere, contracted mesangial cells distort and encroach on the capillary lumen

Answer 719

* The pressure in the glomerular capillaries is higher than that in other capillary beds because the afferent arterioles are short, straight branches of the interlobular arteries. * Furthermore, the vessels "downstream" from the glomeruli, the efferent arterioles, have a relatively high resistance * The capillary hydrostatic pressure is opposed by the hydrostatic pressure in Bowman's capsule * It is also opposed by the onctoic pressure gradient across the glomerular capillaries (π_GC - π_T). π_T is normally negligible and the gradient is essentially equal to the oncotic pressure of the plasma proteins.

Answer 720

* The net filtration pressure (P_UF) is 55mmHg at the afferent end of the glomerular capillaries, but it falls to 0 - filtration equilibrium is reached - proximal to the efferent end of the glomerular capillaries * This is because fluid leaves the plasma and the oncotic pressure rises as blood passes through the glomerular capillaries. * It is apparent that portions of the glomerular capillaries do not normally contribute to the formation of the glomerular ultra filtrate; exchange across the glomerular capillaries is **flow-limited** rather than diffusion limited * A decrease in the rate of rise of the Δ curve produced by an increase in RPF would increase filtration because it would increase the distance along the capillary in which filtration was taking place

Answer 721

* Changes in renal vascular resistance as a result of auto regulation tend to stabilise filtration pressure, but when the mean systemic arterial pressure drops below the auto regulatory range, GFR drops sharply. * The GFR tends to be maintained when efferent arteriolar constriction is greater than afferent constriction, but either type of constriction decreases blood flow to the tubules.

Answer 722

* The ratio of GFR to the RPF, the **filtration fraction**, is normally 0.16-0.20. * The GFR varies less than the RPF. * When there is a fall in systemic blood pressure, the GFR falls less than the RPF because of efferent arteriolar construction, and consequently the filtration fraction rises.

Answer 723

* Changes in renal blood flow * Changes in glomerular capillary hydrostatic pressure * Changes in systemic blood pressure * Afferent or efferent arteriolar constriction * Changes in hydrostatic pressure in Bowman's capsule * Ureteral obstruction * Oedema of kidney inside tight renal capsule * Changes in concentration of plasma proteins: dehydration, hypoproteinaemia, etc * Changes in K_f * Changes in glomerular capillary permeability * Changes in effective filtration surface area

Answer 724

* The amount of any substance (X) that is filtered in the product of the GFR and the plasma level of the substance (C_lnP_X). * The tubular cells may add more of the substance to the filtrate (tubular secretion), may remove some of all of the substance from the filtrate (tubular reabsorption), or may do both

Answer 725

* The amount of the substance excreted per unit of time (V_XV) equals the amount filtered plus the **net amount transferred** by the tubules * This latter quantity is conveniently indicated by the symbol T_X * The clearance of a substance equals the GFR if there is no net tubular secretion or reabsorption, exceeds the GFR if there is net tubular secretion, and is less than the GFR is there is net tubular reabsorption.

Answer 726

* Small proteins and some peptide hormones are reabsorbed in the proximal tubules by endocytosis * Other substances are secreted or reabsorbed in the tubules by passive diffusion between cells and through cells by facilitated diffusion down chemical or electrical gradients. * Movement is by way of ion channels, exchangers, co-transporters, and pumps.

Answer 727

* The pumps and other transporters in the luminal membrane are different from those in the basolateral membrane *It is this polarised distribution that makes possible net movement of solutes across the epithelia

Answer 728

* The amount of a particular solute transported is proportional to the amount present up the Tm for the solute, but at higher concentrations, the transport mechanism is **saturated** and there is no appreciable increment in the amount transported. * However, the Tms for some systems are high, and it is difficult to saturate them

Answer 729

* The tubular epithelium is a **leaky epithelium** in that the tight junctions between cells permit the passage of some water and electrolytes * The degree to which leakage by this **paracellular pathway** contributes to the net flux of fluid and solute into and out of the tubules is controversial since it is difficult to measure, but current evidence seems to suggest that it is a significant factor in the proximal tubule

Answer 730

* In the proximal tubules, the thick portion of the ascending limb of the loop of Henle, the distal tubules, and the collecting ducts, Na⁺ moves by co-transport or exchange from the tubular lumen into the tubular epithelial cells down its concentration and electrical gradients, and is then actively pumped from these cells into the interstitial space * Na⁺ is pumped into the interstitium by Na/K/ATPase in the basolateral membrane * Thus, Na⁺ is actively transported out of all parts of the renal tubule except the thin portions of the loop of Henle.

Answer 731

**Na/glucose co-transporter** - uptakes both glucose and Na⁺ **Na⁺/P_i co-transporter** - Na⁺ and P_I uptake **Na⁺ amino acid co-transporter** - Na⁺ and amino acid uptake **Na/lactate co-transporter** - uptakes Na⁺ and lactate **Na/H exchanger** - Na⁺ uptake and H⁺extrusion **Cl/base exchanger** - Cl^- uptake

Answer 732

**Na/K/2Cl co-transporter** - Na⁺, Cl^- and K⁺ uptake **Na/H exchanger** - Na⁺ uptake, H⁺ extrusion **K⁺ channels** - K⁺ extrusion (recycling)

Answer 733

There is a **NaCl co-transporter** that uptakes both Na⁺ and Cl^-

Answer 734

There is an **ENaC Na⁺ channel** that uptakes sodium

Answer 735

* The tubular cells along the nephron are connected by tight junctions at their luminal edges, but there is space between the cells along the rest of their lateral borders * Much of the Na⁺ is actively transported into these **lateral intercellular spaces**

Answer 736

* Normally about 60% of the filtered Na⁺ is reabsorbed in the proximal tubule, primarily by Na-H exchange. * Another 30% is absorbed via the Na-2Cl-K co-transporter in the thick ascending limb of the loop of Henle * In both of these segments of the nephron, passive paracellular movement of Na⁺ also contributes to overall Na⁺ reabsorption. * In the distal convoluted tubule 7% of the filtered Na⁺ is absorbed by the Na-Cl co-transporter. * The remainder of the filtered Na⁺, about 3% is absorbed via ENaC channels in the collecting ducts and this is the portion that is regulated by aldosterone to permit homeostatic adjustments in Na⁺ balance.

Answer 737

* Glucose is typical of substances removed from the urine by secondary active transport * It is filtered at a rate of approximately 100mg/min. * Essentially all of the glucose is reabsorbed, and no more than a few milligrams spread in the urine per 24 hours.

Answer 738

* The amount reabsorbed is proportional to the amount filtered and hence to the plasma glucose level (P_G) times the GFR up to the transport maximum (Tm_G). * When the Tm_G is exceeded, the amount of glucose in the urine rises. * The Tm_G is about 375mg/min in men and 300mg/min in women

Answer 739

* One would predict that the renal threshold would be about 300mg/dL, that is, 375mg/min (Tm_G) divided by 125ml/min (GFR). * However, the actual renal threshold is about 200mg/dL of arterial plasma, which corresponds to a venous level of about 180mg/dL. * The "ideal" curve would be obtained if the Tm_G in all the tubules was identical and if all the glucose were removed from each tubular when the amount filtered was below the Tm_G. * This is not the case and the actual curve is round and deviates considerably from the "ideal" curve. * This deviation is called **splay**. The magnitude of the splay is inversely proportional to the avidity with which the transport mechanism binds the substrate it transports.

Answer 740

* Glucose reabsorption in the kidneys is similar to glucose reabsorption in the intestine. * Glucose and Na⁺ bind to the sodium-dependent glucose transporter (SGLT-2) in the apical membrane, and glucose is carried into the cells as Na⁺ moves down its electrical and chemical gradient. * The Na⁺ is then pumped out of the cells into the interstitium, and the glucose exits by facilitated diffusion via glucose transporter GLUT-2 into the interstitial fluid.

Answer 741

* SGLT-2 specifically binds the D isomer of glucose, and the rate of transport of D-glucose is many times greater than that of L-glucose * Glucose transport in the kidneys is inhibited, as it is in the intestine, by the plant glucoside **phlorhizin**, which competes the D-glucose for binding to the carrier

Answer 742

* Absorption in this location resembles absorption in the intestine * The main carriers in the apical membrane co-transporter Na⁺, whereas the carriers in the basolateral membranes not Na⁺-dependent. * Na⁺ is pumped out of the cells be Na/K/ATPase and the amino acids leave by passive or facilitated diffusion to the interstitial fluid.

Answer 743

* The filtered load of PAH is a linear function of the plasma level, but PAH secretion increases as P_PAH rises only until a maximal secretion rate (Tm_PAH) is reached. * When P_PAH is low, C_PAH is high; but as P_PAH rises above TM_PAH, C_PAH fall progressively * It eventually approaches the clearance of inulin (C_in) because the amount of PAH secreted becomes a smaller and smaller fraction of the total amount excreted. * Conversely, the clearance of glucose is essentially zero at P_G levels below the renal threshold; but above the threshold, C_G rises to approach C_In as P_G is raised.

Answer 744

* Signals from the renal tubule in each nephron feedback to affect filtration in its glomerulus. * As the rate of flow through the ascending limb of the loop of Hnele and first part of the distal tubule increases, glomerular filtration in the same nephron decreases, and, conversely, a decrease in flow increases the GFR * This process, which is called **tubulo-glomerular feedback**, tends to maintain the constancy of the load delivered to the distal tubule

Answer 745

* The sensor for this response is the **macula densa**. * The amount of fluid entering the distal tubule at the end of the thick ascending limb of the loop of Henle depends on the amount of Na⁺ and Cl^- in it. * The Na⁺ and Cl^- enter the macula densa cells via the Na/K/2Cl co-transporter in their apical membranes * The increased Na⁺ causes increased Na/K/ATPase activity and the resultant increased ATP hydrolysis causes more adenosine to be formed. * Presumably, adenosine is secreted from the basal membrane of the cells

Answer 746

* It acts via adenosine A₁ receptors on the macula densa cells to increase their release of Ca²⁺ to the vascular smooth muscle in the afferent arterioles. * This causes afferent vasoconstriction and a resultant decrease in GFR. * Presumably, a similar mechanism generates a signal that decreases renin excretion by the adjacent juxtaglomerular cells in the afferent arteriole, but this remains unsettled.

Answer 747

* Conversely, an increase in GFR causes an increase in the reabsorption of solutes, and consequently of water, primarily in the proximal tubule, so that in general the percentage of solute reabsorbed is held constant * This process is called **glomerulotubular balance**

Answer 748

The change in Na⁺ reabsorption occurs within seconds after a change in filtration, so it seems unlikely that an extra renal humeral factor is involved.

Answer 749

* When the GFR is high, there is a relatively large increase in the oncotic pressure of the plasma leaving the glomeruli via the efferent arterioles and hence in their capillary branches * This increases the reabsorption of Na⁺ from the tubule.

Answer 750

1) At least 87% of the filtered water is reabsorbed, even when the urine volume is 23L 2) The reabsorption of the remainder of the filtered water can be varied without affecting total solute excretion. Therefore, when the urine is concentrated, water is lost from the body in excess of solute.

Answer 751

* Rapid diffusion of water across cell membranes depends on the presence of water channels, integral membrane proteins called **aquaporins** * 13 aquaporins have been cloned; however one four play a key role in the kidney (aquaporin-1, -2, -3 and -4)

Answer 752

* **Aquaporin-1** is localised to both the basolateral and apical membrane of the proximal tubules * Its presence allows water to move rapidly out of the tubule along the osmotic gradients set up by active transport of solutes, and isotonicity is maintained.

Answer 753

Because the ratio of the concentration in tubular fluid to the concentration in plasma (TF/P) of the non-reabsorbable substance inulin is 2.5 to 3.3 at the end of the proximal tubule, it follows that 60-70% of the filtered solute and 600-70% of the filtered water have been removed by the time the filtrate reaches this point

Answer 754

* There is a graded increase in the osmolality of the interstitium of the pyramids in humans * The osmolality at the tips of the papillae can reach about 1200mOsm/kg of H_{bO, approximately four times that of plasma.
* The fluid in the descending limb of the loop of Henle becomes **hypertonic** as water moves out of the tubule into the hypertonic interstitium.
* When fluid reaches the top of the ascending limb it is now **hypotonic** to plasma.}

Answer 755

* The descending limb of the loop of Henle is permeable to water, due to the presence of **aquaporin-1** in both the apical and basolateral membranes, but the ascending limb is impermeable to water. * Na⁺, K⁺, and Cl^- are co-transported out of the thick segment of the ascending limb. * Therefore the fluid in the descending limb of the loop of Henle becomes **hypertonic** as water moves out of the tubule into the hypertonic interstitium. * In the ascending limb it becomes more dilute because of the movement of Na⁺ and Cl^- out of the tubular lumen, and when fluid reaches the top of the ascending limb (called the **diluting segment** it is now hypotonic to plasma.

Answer 756

* A carrier co-transports them via secondary active transport * The Na⁺ is actively transported from the cells into the interstitium by Na/K/ATPase in the basolateral membranes of the cells, keeping the intracellular Na⁺ low.

Answer 757

* The K⁺ diffuses back into the tubular lumen and back into the interstitium via ROMK and other K⁺ channels * The Cl^- moves into the interstitium via ClC-Kb channels

Answer 758

* The distal tubule, particularly its first part, is in effect an extension of the thick segment of the ascending limb * It is relatively impermeable to water, and continued removal of the solute in excess of solvent further dilutes the tubular fluid

Answer 759

A cortical portion and a medullary portion

Answer 760

* They depend on the amount of vasopressin acting on the ducts. * This anti-diuretic hormone from the posterior pituitary gland increases the permeability of the collecting ducts to water.

Answer 761

* Aquaporin-2 is stored in vesicles in the cytoplasm of principal cells. * Vasopressin causes rapid insertion of these vesicles into the apical membrane of cells * The effect is mediated via the vasopressin V₂ receptor, cAMP and protein kinase A. * Cytoskeletal elements are involved, including microtubule-based motor proteins (dynein and dynactin) as well as actin-filament binding proteins such as myosin-1

Answer 762

* Water moves out of the hypotonic fluid entering the cortical collecting ducts into the interstitium of the cortex, and tubular fluid becomes isotonic * In this manner, as much as 10% of the filtered water is removed * The isotonic fluid then enters the medullary collecting ducts with a TF/P inulin of about 20. * An additional 4.7% or more of the filtrate is reabsorbed into the hypertonic interstitium of the medulla, producing a concentrated urine with a TF/P inulin of over 300.

Answer 763

The osmolality of urine may reach 1400mOsm/kg of H₂, almost five times the osmolality of plasma, with a total of 99.7% of the filtered water being reabsorbed

Answer 764

* When vasopressin is absent, the collecting duct epithelium is relatively impermeable to water. * The fluid therefore remains hypotonic, and large amounts flow into the renal pelvis * The impermeability of the distal portions of the nephron is not absolute; along with the salt that is pumped out of the collection duct fluid, about 2% of the filtered water is reabsorbed in the absence of vasopression

Answer 765

* It depends on the maintenance of a gradient of **increasing osmolality** along the medullary pyramids. * This gradient is produced by the operation of the loops of Henle as **countercurrent multipliers** and maintained by the operation of the vasa recta as **countercurrent exchangers**. * A countercurrent system is a system in which the inflow runs parallel to, counter to, and in close proximity to the outflow for some distance * This occurs for both the loops of Henle and the vasa recta in the renal medulla

Answer 766

It depends on the high permeability of the thin descending limb to water (via aquaporin-1), the active transport of Na⁺ and Cl^- out of the thick ascending limb, and the inflow of tubular fluid from the proximal tubule, with outflow into the distal tubule.

Answer 767

* Assume first a condition in which osmolality is 300mOsm/kg of H₂O throughout the descending and ascending limbs and the medullary interstitium (A) * The pumps in the thick ascending limb pump 100 mOsm/kg of Na⁺ and Cl^- from the tubular fluid to the interstitium, increasing interstitial osmolality to 400 mOsm/kg of H₂O. (B) * Water then moves out of the thin descending limb, and its content equilibrate with the interstitium. (B) * However, fluid containing 300 mOsm/kg H₂O is continuously entering this limb from the proximal tubule, so the gradient against which the Na⁺ and Cl^- are pumped is reduced and more enters the interstitium (C) * Meanwhile, hypotonic fluid flows into the distal tubule, and isotonic and subsequently hypertonic fluid flows into the ascending thick limb (D) * The process keeps repeating, and the final result is a gradient of osmolality from the top to the bottom of the loop

Answer 768

* In juxtamedullary nephrons with longer loops and thin ascending limbs, the osmotic gradient is spread over a greater distance and the osmolality at the top of the loop is greater. * This is because the thin ascending limb is relatively impermeable to water but permeable to Na⁺ and Cl^-. Therefore, Na⁺ and Cl^- move down their concentration gradients into the interstitium, and there is additional passive countercurrent multiplication. * The greater the length of the loop of Henle, the greater the osmolality that can be reached at the tip of the medulla

Answer 769

* The solutes diffuse out of the vessels conducting blood toward the cortex and into the vessels descending into the pyramid * Conversely, water diffuses out of the descending vessels and into the fenestrated ascending vessels. * Therefore, the solutes tend to recirculate in the medulla and water tends to bypass it, so that hypertonicity is maintained. * The water removed form the collecting ducts in the pyramids is also removed by the vasa recta and enters the general circulation * Countercurrent exchange is a passive process; it depends on movement of water and could not maintain the osmotic gradient along the pyramids if the process of counter-current multiplication in the loops of Henle were to cease

Answer 770

Urea contributes to the establishment of the osmotic gradient in the medullary pyramids and to the ability to form a concentrated urine in the collecting ducts.

Answer 771

* UT-A1 to UT-A4 are found in the kidneys * UT-B is found in erythrocytes and in the descending limb of the vasa recta * Urea transport in the collecting duct is mediated by UT-A1 and UT-A3, and both are regulated by vasopressin

Answer 772

* During anti-diuresis, when vasopressin is high, the amount of urea deposited in the medullary interstitium increases, thus increasing the concentrating capacity of the kidney. * In addition, the amount of urea in the medullary interstitium and, consequently, in the urine varies with the amount of urine filtered, and this in turn varies with the dietary intake of protein * Therefore, a high-protein diet increases the ability of the kidneys to concentrate the urine and a low-protein diet reduces the kidney's ability to concentrate the urine

Answer 773

* The presence of large quantities of unreabsorbed solutes in the renal tubules causes an increase in urine volume called **osmotic diuresis**. * Solutes that are not reabsorbed in the proximal tubules exert an appreciable osmotic effect as the volume of tubular fluid decreases and their concentration rises. * Therefore, they "hold water in the tubules"

Answer 774

* The concentration against which Na⁺ can be pumped out of the proximal tubule is limited. Normally, the movement of water out of the proximal tubule prevents any appreciable gradient from developing * But Na⁺ concentration in the fluid falls when water reabsorption is decreased because of the presence in the tubular fluid of increased amounts of unreabsorbable solutes * The limiting concentration gradient is reached, and further proximal reabsorption of Na⁺ is prevented; more Na⁺ remains in the tubule and water stays with it. * The result is that the loop of Henle is presented with a greatly increased volume of isotonic fluid. * This fluid has a decreased Na⁺ concentration, but the total mount of Na⁺ reaching the loop per unit time is increased

Answer 775

* The decrease is due primarily to decreased reabsorption of Na⁺, K⁺, and Cl^- in the ascending limb of the loop because the limiting concentration gradient for Na⁺ reabsorption is reached. * More fluid passes through the distal tubule, and because of the decrease in the osmotic gradient along the medullary pyramids, less water is reabsorbed in the collecting ducts. * The result is a marked increase in urine volume and excretion of Na⁺ and other electrolytes

Answer 776

* Osmotic diuresis is produced by the administration of compounds such as mannitol and related polysaccharides that are filtered but not reabsorbed * It is also produced by naturally occurring substances when they are present in amount exceeding the capacity of the tubules to resorb them. For example, in diabetes mellitus, if blood glucose is high, glucose in the glomerular filtrate if high, thus the filtered load with exceed the Tm_G and glucose will remain the tubules causing polyuria. * Osmotic diuresis can also be produced by the infusion of large amounts of sodium chloride or urea.

Answer 777

* In water diuresis, the amount of water reabsorbed in the proximal portions of the nephron is normal, and the maximum urine flow that can be produced in about 16mL/min * In osmotic diuresis, increased urine flow is due to decreased water reabsorption in the proximal tubules and loops and very large urine flows can be produced. As the load of excreted solute is increased, the concentration of the urine approaches that of plasma in spite of maximum vasopressin secretion, because an increasingly large fraction of the excreted urine is isotonic proximal tubular fluid. If osmotic diuresis is produced with diabetes insipidus, the urine concentration rises for the same reason

Answer 778

* The magnitude of the osmotic gradient along the medullary pyramids is increased when the rate of flow of fluid through the loops of Henle is decreased. * A reduction in GFR such as that caused by dehydration produces a decrease in the volume of fluid presented to the countercurrent mechanism, so that the rate of flow in the loops declines and the urine becomes more concentrated * When the GFR is low, the urine can become quite concentrate in the absence of vasopressin * If one renal artery is constricted with a patient with diabetes insipidus, the urine excreted on the side of the constriction becomes hypertonic because of the reduction in GFR, whereas that excreted on the opposite side remains hypotonic.

Answer 779

* In order to quantitate the gain or loss of water by excretion of a concentrated or dilute urine, the "free water clearance" (C_H₂O) is sometimes calculated. * This is the difference between the urine volume and the clearance of the osmoles.

Answer 780

* Normally about 99% of the filtered Na⁺ is reabsorbed * Because Na⁺ is the most abundant cation in ECF and because Na⁺ salts account for over 90% of the osmotically active solute in the plasma and interstitial fluid, the amount of Na⁺ in the body is a prime determinant of the ECF volume.

Answer 781

* Through the operation of these regulatory mechanisms, the amount of Na⁺ excreted is adjusted to equal the amount ingested over a wide range of dietary intakes, and the individual stays in Na⁺ balance. * When Na⁺ intake is high, or saline is infused, natriuresis occurs, whereas when ECF is reduced, a decrease in Na⁺ excretion occurs

Answer 782

Urinary Na ⁺ output ranges from less than 1mEq/day on a low-salt diet to 400 mEq/day or more when the dietary Na⁺ intake is high

Answer 783

* Changes are primarily in the 3% of filtered Na⁺ that reached the collecting ducts * Factors affecting Na⁺ reabsorption include the the circulating level of aldosterone and other adrenocortical hormones, the circulating level of ANP and other natriuretic hormones, and the rate of tubular secretion of H⁺ and K⁺

Answer 784

* Adrenal mineralocorticoids such as aldosterone increase tubular reabsorption of Na⁺ in association with secretion of K⁺ and H⁺ and also Na⁺ reabsorption with Cl^- * They take around 10-30 minutes to occur because of the time required for the steroids to alter protein synthesis via their action on DNA * The mineralocorticoids act primarily in the collecting ducts to increase the number of active epithelial sodium channels (ENaCs) in this part of the nephron.

Answer 785

* Mutations in the genes that code for the β subunit and less commonly the γ subunit of ENaC cause the channels to come constitutively active in the kidney * This leads to Na⁺ retention and hypertension

Answer 786

PGE₂ causes a natriuresis, possibly by inhibiting Na/K/ATPase and possibly by increasing intracellular Ca²⁺, which in turn inhibits Na⁺ transport via ENaCs

Answer 787

Endothelin and IL-1 cause natriuresis, probably by increasing the formation of PGE₂

Answer 788

* Angiotensin II increases reabsorption of Na⁺ and HCO₃^- by an action on the proximal tubules * There is an appreciable amount of ACE in the kidney in the kidneys, and the kidneys convert 20% of the circulating angiotensin I to angiotensin II. * In addition, angiotensin I is generated in the kidneys

Answer 789

* Prolonged exposure to high levels of circulating mineralocorticoids does not cause oedema in otherwise normal individuals because eventually the kidneys escape from the effect of the steroids * This is due to **escape phenomenon**, which may be due to increased secretion of ANP. * It appears to be reduced or absent in nephrosis, cirrhosis, and heart failure, and patients with these diseases continue to retain Na⁺ and become oedematous when exposed to high levels of mineralocorticoids

Answer 790

* The water diuresis produced by drinking large amounts of hypotonic fluid begins about 15 mintues after ingestion of a water load and reaches its maximum un about 40 minutes. * The act of drinking produces a small decrease in vasopressin secretion before the water is absorbed, but most of the inhibition is produced by the decrease in plasma osmolality after the water is absorbed.

Answer 791

* Much of the filtered K⁺ is removed from the tubular fluid by active reabsorption in the proximal tubules, and K⁺ is then secreted into the fluid by the distal tubular cells * The rate of K⁺ secretion is proportional to the rate of flow of the tubular fluid through the distal portions of the nephron, because its rapid flow there is loss opportunity for the tubular K⁺ concentration to rise to a value that stops further secretion

Answer 792

* In the collecting ducts, Na⁺ is generally reabsorbed and K⁺ is secreted. * There is not rigid one-for-exchange and much of the movement of K⁺ is passive. * However, there is electrical coupling in the sense that intracellular migration of Na⁺ from the lumen tends to lower the potential difference across the tubular cell, and this favours movement of K⁺ into the tubular lumen * K⁺ excretion is decreased when the amount of Na⁺ reaching the distal tubule is small. * In addition, if H⁺ secretion is increased, K⁺ excretion will decrease as K⁺ is reabsorbed in collecting duct cells in exchange for H⁺ via the action of the H/K/ATPase.

Answer 793

* The ability to forma dilute urine is often retained, but in advanced kidney disease, the osmolality of the urine becomes fixed at about that of plasma, indicating that the diluting and concentrating functions of the kidney have both been lost * The loss is due in part to disruption of the countercurrent mechanism, but a more important cause is a loss of functioning nephrons.

Answer 794

* When one kidney is removed surgically, the number of functioning nephrons is halved. * The number of osmoles to be excreted is not reduced to this extent, and so the remaining nephrons must each by filtering and exerting more osmotically active substances, producing what is in effect an osmotic diuresis * In osmotic diuresis, the osmolality of the urine approaches that of plasma. The same thing happens when the number of functioning nephrons is reduced by disease. * The increased filtration in the remaining nephrons eventually damages them, and thus more nephrons are lot.

Answer 795

* The symptoms of uraemia include lethargy, anorexia, nausea and vomiting, mental deterioration and confusion,a nd muscle twitching, convulsions and come * The blood urea nitrogen (BUN) and creatinine levels are high, and the blood levels of these substances are used as an index of the severity of the uraemia * It probably is not the accumulation of urea and creatinine that is causing the symptoms, but rather the accumulation of other toxic substances.

Answer 796

* The toxic substances that cause the symptoms of uraemia can be removed by dialysing the blood of uraemia patients against a bath of suitable composition in an artificial kidney (**haemodialysis**). * Patients can be kept alive and in reasonable health for many months of dialysis, even when they are completely anuric or have had both kidneys removed * However, the treatment of choice today is certainly transplantation

Answer 797

1) In acute glomerulonephritis, the amount of Na⁺ filtered is decreased markedly 2) In the nephrotic syndrome, an increase in aldosterone secretion contributes to salt retention. The plasma protein level is low in this conditioner and so fluid moves from the plasma into the interstitial spaces and the plasma volume falls. The decline in plasma volume triggers an increase in aldosterone secretion via the renin-angiotensin system 3) Heart failure - kidney disease predisposes to heart failure, partly because of the hypertension it frequently produces

Answer 798

* The walls of the ureters contain smooth muscle arranged in spiral, longitudinal and circular bundles, but distinct layers of muscle are not seen. * Regular peristaltic contractions occurring one to five times per minute move the urine from the renal pelvis to the bladder, where it enters in spurts synchronous with each peristaltic wave * The ureters pass obliquely through the bladder wall and, although there are no ureteral sphincters as such, the oblique passage tends to keep the ureters closed except during peristaltic waves, preventing reflux of urine from the bladder

Answer 799

* The smooth muscle of the bladder, like that of the uterus, is arranged in spiral, longitudinally and circular bundles * Contraction of the circular muscle, which is called the **detrusor muscle**, is mainly responsible for emptying the bladder during urination

Answer 800

* Muscle bundles pass on either side of the urethra, and these fibers are sometimes called the **internal urethral sphincter**, although they do not encircle the urethra * Farther along the urethra is a sphincter of skeletal muscle, the sphincter of the membranous urethra (**external urethral sphincter**).

Answer 801

* The bladder epithelium is made up of a superficial layer of flat cells and a deep layer of cuboidal cells * The innervation of the bladder is by the pelvic, pudendal and hypogastric nerves

Answer 802

Micturition is fundamentally a spinal reflex facilitated and inhibited by higher brain centres and, like defecation, subject to voluntary facilitation and inhibition.

Answer 803

* Urine enters the bladder without production much increase in intravesical pressure until the viscus is well filled. * In addition, like other types of smooth muscle, the bladder muscle has the property of plasticity; when it is stretched, the tension initially produced is not maintained.

Answer 804

* A plot of intravesical pressure against the volume of fluid in the bladder is called a **cystometrogram** * The curve shows an initial slight rise in pressure when he first increments in volume are produced; a long, nearly flat segment as further increments are produced; and a sudden sharp rise in pressure as the micturition reflex is triggered. * These three components are sometimes called segments Ia, Ib and II

Answer 805

* The first urge to void is felt at a bladder volume of about 150ml * A marked sense of fullness at about 400mL

Answer 806

* This law states the the pressure in a spherical viscus is equal to twice the wall tension divided by the radius * In the case of the bladder, the tension increases as the organ fills, but does the radius. * Therefore, the pressure increase is slight until the organ is relatively full

Answer 807

* During micturition, the perineal muscles and external urethral sphincter are relaxed, the detrusor muscle contracts, and urine passes out through the urethra. * The bands of smooth muscle on either side of the urethra apparently play no role in micturition and their main function in males is believed to be the prevention of reflux of semen into the bladder during ejaculation

Answer 808

* One of the initial events is relaxation of the muscles of the pelvic floor, and this may cause a sufficient downward tug on the detrusor muscle to initiate its contraction * The perineal muscles and external sphincter can be contracted voluntarily, preventing urine from passing down the urethra or interrupting the flow once urination has begun

Answer 809

* In females, the urethra empties by gravity * Urine remaining in the urethra of the male is expelled by several contractions of the bulbocavernosus muscle

Answer 810

* Stretch receptors in the bladder wall initiate a reflex contraction that has a lower threshold than the inherent contractile response of the muscle * Fibers in the pelvic nerves are the afferent limb of the voiding reflex, and the parasympathetic fibers to the bladder that constitute the efferent limb also travel in these nerves. * The reflex is integrated in the sacral portion of the spinal cord.

Answer 811

* The sympathetic nerves to the bladder play no part in micturition * But in males they do mediate the contraction of the bladder muscle that prevents semen from entering the bladder during ejaculation.

Answer 812

There is a facilitatory area in the potion region and an inhibitory area in the midbrain

Answer 813

* After transection of the brainstem just above the pons, the threshold for voiding is lowered and less bladder filling is required to trigger it * After transection at the top of the midbrain, the threshold for the reflex is essentially normal * Patients with lesions in the superior frontal gyrus have a reduced desire to urinate and difficulty in stopping micturition once it has commenced.

Answer 814

* There are effects of deafferentation * All reflex contractions of the bladder are abolished. * The bladder becomes distended, thin-walled and hypotonic, but some contractions occur because of the intrinsic response of the smooth muscle to stretch

Answer 815

* There are effects of denervation * The bladder is flaccid and distended for a while * Gradually however, the muscle of the "decentralised bladder" becomes active, with many contraction waves that expel dribbles of urine out of the urethra * The bladder becomes shrunken and the bladder wall hypertrophied

Answer 816

* During spinal shock, the bladder is flaccid and unresponsive. It becomes overfilled, and urine dribbles through the sphincters (**overflow incontinence**). * After spinal shock has passed, the voiding reflex returns, although there is, of course, no voluntary control and no inhibition or facilitation from higher centres when the spinal cord is transected.

Answer 817

In the some instances of paraplegia, the voiding reflex becomes hyperactive, bladder capacity is reduced, and the wall becomes hypertrophied

Answer 818

Vasopressin-secretion and third mechanisms

Answer 819

* The total body osmolality is directly proportional to the total body sodium plus the total body potassium divided by the total body water * Changes in the osmolality of the body fluids occur when a mismatch exists between the amount of these electrolytes and the amount of water ingested or lost from the body

Answer 820

* Vasopressin secretion is increased and the thirst mechanism is stimulated * Water is retained in the body, diluting the hypertonic plasma * Water intake is increased

Answer 821

* Vasopressin secretion is decreased and "solute-free water" (water in excess of solute) is excreted

Answer 822

* Plasma osmolality ranges from 280mOsm/kg of H₂O to 295mOsm/kg of ₂ * Vasopressin secretion is maximally inhibited at 285mOsm/kg and stimulated at higher values

Answer 823

* V_1A, V_1B, and V₂ * All are G-protein coupled * The V_1A and V_1B receptors act through phosphatidylinositol hydrolysis to increase the intra-cellular Ca²⁺ concentration. * The V₂ receptors act through G_S to increase cAMP levels

Answer 824

* Because one of its principal physiologic effects is the retention of water by the kidney, vasopressin is often called the **anti-diuretic hormone (ADH)**. * It increases the permeability of the collecting ducts of the kidney, so that water enters the hypertonic interstitium of the renal pyramids * The urine becomes concentrated, and its volume decreases. * The overall effect is therefore retention of water in excess of solute; consequently, the effective osmotic pressure of the body fluids is decreased.

Answer 825

* It is activated by V₂ receptors and involves the insertion of aquaporin 2 into the apical (luminal) membranes of the principal cells of the collecting ducts * Movement of water across membranes by simple diffusion is now known to be augmented by movement through these water channels. * These channels are stored in endosomes inside the cells, and vasopressin causes their rapid translocation to the luminal membranes.

Answer 826

* V_1A receptors mediate the vasoconstrictor effect of vasopressin, and vasopressin is a potent stimulator of vascular smooth muscle in vitro. * However, relatively large amounts of vasopressin are needed to raise blood pressure in vivo, because vasopressin also acts on the brain to decrease in cardiac output * The site of this action is the **area postrema**, one of the circumventricular organs.

Answer 827

* Haemorrhage is a potent stimulus for vasopressin secretion * The blood pressure fall after haemorrhage is more marked in animals that have been treated with synthetic peptides that block the pressor action of vasopressin * Consequently, it appears that vasopressin does play a role in blood pressure homeostasis

Answer 828

* V_1A receptors are also found in the liver, and the brain * It causes glucogenolysis in the liver, and is a neurotransmitter in the brain and spinal cord

Answer 829

The V_1B receptors appear to be unique to the anterior pituitary, where they mediate increased secretion of ACTH from the corticotropes

Answer 830

* Circulating vasopressin is rapidly inactivated, principally in the liver and kidney * It has a biologic half-life of approximately 18 minutes in humans

Answer 831

* Vasopressin is stored in the posterior pituitary and released into the bloodstream in response to impulses in the nerve gibers that contain the hormone * When the effective osmotic pressure of the plasma is increased above 285 mOsm/kg, the rate of discharge of neurons containing vasopressin increases and vasopressin secretion occurs. * Vasopressin secretion is regulated by osmoreceptors located in the anterior hypothalamus. They are outside the blood-brain barrier and appear to be located in the circumventricular organs, primarily the organum vasculosum of the lamina terminalis (OVLT)

Answer 832

The osmotic threshold for thirst is the same or slightly greater than the threshold for increased vasopressin secretion, and it is still uncertain whether the same osmoreceptors mediate both effects.

Answer 833

Vasopressin secretion is increased when ECF volume is low and decreased when ECF volume is high

Answer 834

* There is an inverse relationship between the rate of vasopressin secretion and the rate of discharge in afferents from stretch receptors in the low- and high-pressure portions of the vascular system * The low-pressure receptors are this in the great veins, right and left atria, and the pulmonary vessels; the high pressure-receptors are this sin the carotid sinuses and aortic arch * However, the low-pressure receptors monitor the fullness of the vascular systems and moderate decreases in blood volume that reduce central venous pressure without lowering arterial pressure can also increase plasma vasopressin

Answer 835

* Impulses pass from them via the vagi to the nucleus of the tracts solitarius (NTS). * An inhibitory pathway projects from the NTS to the caudal ventrolateral medulla (CVLM), and there is a direct excitatory pathway from the CVLM to the hypothalamus * Angiotensin II reinforces the response to hypovolaemia and hypotension by acting on the circumventricular organs to increase vasopressin secretion

Answer 836

* Hypovolaemia and hypotension produced by conditions such as haemorrhage release large amounts of vasopressin, and in the presence of hypovolaemia, the osmotic response curve is shifted to the left. * Its slope is also increased. The result is water retention and reduced plasma osmolality. * This includes hyponatraemia, since Na⁺ is the most abundant osmotically active component of the plasma

Answer 837

**Vasopressin secretion increased** * Increased effective osmotic pressure of plasma * Decreased ECF volume * Pain, emotion, "stress", exercise * Nausea and vomiting * Standing * Carbamazepine, angiotensin II **Vasopressin secretion decreased** * Decreased effective osmotic pressure of plasma * Increased ECF volume * Alcohol

Answer 838

**Diabetes insipidus** is the syndrome that results when there is a vasopressin deficiency (**central diabetes insipidus**) or when the kidneys fail to respond to the hormone (**nephrogenic diabetes insipidus**)

Answer 839

* These include disease processes in the supraoptic and paraventricular nuclei, the hypothalamohypophysial tract, or the posterior pituitary gland * It has been estimated that 30% of clinical cases are due to neoplastic lesions of the hypothalamus, either primary or metastatic; 30% are post-traumatic; 30% are idiopathic; and the remainder are due to vascular lesions, infections, systemic diseases such as sarcoidosis that affect the hypothalamus, or mutations in the gene for prepropressophysin.

Answer 840

Disease that develops after surgical removal of the posterior lobe of the pituitary may be termporary if the distal ends of the supraoptic and paraventricular fibers are only damaged, because the fibers recover, make new vascular connections and begin to secrete vasopressin again

Answer 841

* The symptoms of diabetes insipidus are passage of large amounts of dilute urine (**polyuria**) and the drinking of large amounts of fluid (**polydipsia**), provided the thirst mechanism is intact * It is the polydipsia that keeps these patients healthy * If their sense of thirst is depressed for any reason and their intake of dilute fluid decreases, dehydration that can be fatal develops

Answer 842

* In one form, the gene for the V₂ receptor is mutated, making the receptor unresponsive. The V₂ receptor is on the X chromosome, thus this condition is X-linked and inheritance is sex-linked recessive * In the other form of the condition, mutations occur in the autosomal gene for aquaporin-2 and produce non-functional versions of this water channel, many of which do not reach the apical membrane of the collecting duct but are trapped in intracellular locations

Answer 843

* Synthetic peptides that have selective actions and are more active than naturally occurring vasopressin have been produced by altering the amino acid residues * For example, 1-deamino-8-D-arginine vasopressin (desmopressin) has a very high antidiuretic activity with little pressor activity, making it valuable in the treatment of vasopressin deficiency

Answer 844

Volume stimuli override the osmotic regulation of vasopressin secretion

Answer 845

* It stimulates aldosterone and vasopressin secretion * It also causes thirst and constricts blood vessels, which help maintain blood pressure. Thus, angiotensin II plays a key role in the body's response to hypovolaemia

Answer 846

Expansion of the ECF volume increases the secretion of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) by the heart, and this causes natriuresis and diuresis.

Answer 847

* In disease sates, loss of water from the body (dehydration) causes a moderate decrease in ECF volume, because water is lost from both the intracellular and ECF compartments; but excessive loss of Na⁺ in the tools (diarrhoea), urine (severe acidosis, adrenal insufficiency), or sweat (heat prostration) decreases ECF volume markedly and eventually leads to shock * The immediate compensations in shock operate principally to maintain intravascular volume, but they also affect Na⁺ balance.

Answer 848

In adrenal insufficiency, the decline in ECF volume is not only due to loss of Na⁺ in the urine but also to its movement into cells

Answer 849

* When ECF volume is decreased, blood pressure falls, glomerular capillary pressure declines, and the glomerular filtration rate therefore falls, reducing the amount of Na⁺ filtered. * Tubular reabsorption of Na⁺ is increased, in part because the secretion of aldosterone is increased. * Aldosterone secretion is controlled in part by a feedback system in which the change that initiates increased secretion is a decline in mean intravascular pressure.

Answer 850

* The muscle cells in the atria and, to a much lesser extent in the ventricles, contain secretory granules. * The granules increase in number when NaCl intake is increased and ECF expanded, and extracts of atrial tissue cause natriuresis

Answer 851

In the heart mainly and in the brain, where it exists in two forms that are smaller than circulating ANP

Answer 852

It is also present in the brain, but more is present in the human heart, including the ventricles.

Answer 853

* It is present in the brain, the pituitary, the kidneys, and vascular endothelial cells. * However, very little is present in the heart and the circulation, and it appears to be primarily a paracrine mediator

Answer 854

* ANP and BNP in the circulation act on the kidneys to increase Na⁺ excretion. * They appear to produce this effect by dilating afferent arterioles and relaxing mesangial cells. Both of these actions increase glomerular filtration. * In addition, they act on the renal tubules to inhibit Na⁺ reabsorption. * Other actions include an increase in capillary permeability, leading to extravasation of fluid and a decline in blood pressure * In addition, they relax vascular smooth muscle in arterioles and venules * They also inhibit renin secretion and counteract the pressor effects of catecholamines and angiotensin II.

Answer 855

* An ANP-containing neural pathway projects from the anteromedial part of the hypothalamus to the areas in the lower brainstem that are concerned with neural regulation of the cardiovascular system * In general, the effects of ANP in the brain are opposite to those of angiotensin II, and ANP-containing neural circuits appear to be involved in counteracting the effects of vasopressin and angiotensin II, promoting natruiresis

Answer 856

* The NPR-A and NPR-B receptors both span the cell membrane and have cytoplasmic domains that are guanylyl cyclases. * ANP has the greatest affinity for the NPR-A receptor, and CNP has the greatest affinity for the NPR-B receptor * The third receptor, NPR-C, binds to all three natriuretic peptides but has a markedly truncated cytoplasm domain. There is debate if it is a clearance receptor to clear the peptides or if it acts via G-proteins to activate phospholipase C and inhibit adenylyl cyclase

Answer 857

* The concentration of ANP in plasma is about 5 fmol/mL in normal humans ingesting moderate amounts of NaCL * ANP secretion is increased when the ECF volume is increased by infusion of isotonic saline and when the atria are stretched. * It is also increase by immersion in water up to the neck, a procedure that counteracts the effect of gravity on the circulation and increases central venous and consequently atrial pressure * A small but measurable decrease in plasma ANP occurs in association with a decrease in central venous pressure eon rising from the supine to the standing position. * Thus, the rate of ANP secretion is proportional to the degree to which the atria are stretched by increased in central venous pressure

Answer 858

* When the ventricles are stretched. * Plasma levels of both ANP and BNP are elevated in heart failure

Answer 859

It decreases the secretion of renin and aldosterone because it counteracts the effect of gravity on the circulation and increases central venous pressure

Answer 860

* These adjustments are brought about changes in the circulating level of **erythropoietin**.

Answer 861

* It increases the number of erythropoietin-sensitive stem cells in the bone marrow that are converted to red blood cell precursors and subsequently to mature erythrocytes

Answer 862

* The receptor for erythropoietin is a linear protein with a single transmembrane domain that is a member of the cytokine receptor superfamily * The receptor has tyrosine kinase activity, and it activates a cascade of serine and threonine kinases, resulting in inhibited apoptosis of red cells and their increased growth and development

Answer 863

* The principal site of inactivation of erythropoietin is the liver, and the hormone has a half-life in the circulation of about 5 hours * However, the increase in circulating red cells that is triggers takes 2-3 days to appear, since red cell maturation is a relatively slow process.

Answer 864

* In adults, about 85% of the erythropoietin comes from the kidneys and 15% from the liver. Both these organs contain the mRNA for erythropoietin * It can also be extracted from the spleen and salivary glands, but these tissues do not contain its mRNA and consequently do not appear to manufacture the hormone. * When renal mass is reduced, in adults by kidney disease or nephrectomy, the liver cannot compensate and anaemia develops

Answer 865

It is produced by interstitial cells in the peritubular capillary bed of the kidneys and be perivenous hepatocytes in the liver.

Answer 866

* It is produced in the brain, where it exerts a protective effect against excitotoxic damage triggered by hypoxia * It is also produced in the uterus and oviducts, where it is induced by oestrogen and appears to mediate oestrogen-dependent angiogenesis

Answer 867

* Recombinant erythropoietin produced in animal cells is available for clinical use as epoetin alfa. * It is of value in the treatment of the anaemia associated with kidney failure * It is also used to stimulate red cell production in individuals who are baking a supply of their own blood in preparation for autologous transfusions during elective surgery

Answer 868

* The usual stimulus for erythropoietin secretion is hypoxia, but secretion of the hormone can also be stimulated by cobalt salts and androgens * The O₂ sensor regulating erythropoietin secretion in the kidneys and the liver is a gene protein that in the deoxy form stimulates and in the oxy form inhibits transcription of the erythropoietin gene to form erythropoietin mRNA. * Secretion of the hormone is also facilitated by the alkalosis that develops at high altitudes * Like renin secretion, erythropoietin secretion is facilitated by catecholamines via a β-adrenergic mechanism

Answer 869

* The cells of the proximal and distal tubules, like the cells of the gastric glands, secrete hydrogen ions * Hydrogen secretion also occurs in the collecting ducts. in exchange for Na⁺

Answer 870

* The transporter that is responsible for H⁺ secretion in the proximal tubules is the Na-H exchanger (primarily NHE3). * This is an examples of secondary active transport; Na⁺ is moved from the inside of the interstitium by Na/K/ATPase on the basolateral membrane, which keeps intracellular Na⁺ low, thus establishing the drive for Na⁺ to enter the cell, via the Na⁺ exchanger, from the tubular lumen. * The Na/H exchanger secretes H⁺ into the lumen

Answer 871

* The secreted H⁺ ion combines with filtered HCO₃^- to form H₂CO₃ * The presence of carbonic anhydrase on the apical membrane of the proximal tubule catalyses the formation of H₂O and CO₂ from H₂CO₃ * The apical membrane of epithelial cells lining the proximal tubule is permeable to CO₂ and H₂O, and they enter the tubule rapidly * 80% of the filtered load of HCO₃^-. is reabsorbed in the proximal tubule

Answer 872

* It can catalyse the formation of H₂CO₃ from CO₂ and H₂O. * H₂CO₃ dissociates into H⁺ ions and HCO₃^- * The H⁺ is secreted into the tubular lumen, via the Na-H exchanger and the HCO₃^- that is formed diffuses into the interstitial fluid * Thus, for each H⁺ ion secreted, one Na⁺ ion and one HCO₃^- enter the interstitial fluid.

Answer 873

* H⁺ is relatively independent of Na⁺ in the tubular lumen, * In this part of the tubule, most H⁺ is secreted by an ATP-driven proton pump * The I cells in this part of the renal tubule secrete acid and contain abundant carbonic anhydrase and numerous tubulovesicular structures. * H⁺-translocating ATPase that produced H⁺ secretion is located in this vesicles as well as in the apical cell membrane * Some of the H⁺ is additionally secreted by H/K⁺/ATPase

Answer 874

Aldosterone acts on this pump to increase distal H⁺ secretion

Answer 875

The H⁺ translocating ATPase that produces H⁺ secretion is located in vesicles in the distal tubules and collecting ducts as well as in the apical cell membrane and, in acidosis the number of H⁺ pumps is increased by insertion of these tubulovesicles into the apical cell membrane

Answer 876

* Anion exchanger 1 is an anion exchange protein in the I cell basolateral cell membrane. * It may function as a Cl-HCO₃ exchanger for the transport of HCO₃^- to the interstitial fluid

Answer 877

* The maximal H⁺ gradient against which the transit mechanisms can secrete corresponds to a urine pH of about 4.5; that is, an H⁺ concentration in the urine that is 1000 times the concentration in plasma. * pH 4.5 is thus the limiting pH. This is normally reached in the collecting ducts. * If there were no buffers that "tied up" H⁺ in the urine, this pH would be reached rapidly, and H⁺ secretion would stop. * However, three important reactions in the tubular fluid remove free H⁺, permitting more acid to be secreted. * These are the reactions of H⁺ with: HCO₃^- to form CO₂ and H₂); HPO₄^2- to form H₂PO₄^-; and with NH₃ to form NH₄⁺.

Answer 878

* Approximately 40% of non-volatile acids is excreted as **titratable acid** (i.e. phosphate system) * 60% of non-volatile acid is excreted as HN₄⁺.

Answer 879

* The concentration of HCO₃^- in the plasma, and consequently in the glomerular filtrate, is normally about 24 mEg/L, whereas that of phosphate is only 1.5mEq/L * Therefore, in the proximal tubular, most of the secreted H⁺ reacts with HCO₃

to form H₂CO₃ and this enters the cell as CO₂ and H₂O following the action of carbonic anhydrase in the brush border of the proximal tubule cells.

Answer 880

* The CO₂ entering the tubular cells adds to the poor of CO₂ available to form H₂CO₃ * Because most of the H⁺ is removed from the tubule, the pH of the fluid is changed very little * For each more of HCO₃^- removed from the tubular fluid, 1 mol of HCO₃^- diffuses from the tubular cells into the blood

Answer 881

* This happens to the greatest extent in the distal tubules and collecting ducts * It is here that the phosphate that escapes the proximal reabsorption is greatly concentrated by the reabsorption of water

Answer 882

* The ammonia buffering system allows secreted H⁺ to combine with NH₃ * This occurs in the proximal tubule and in the distal tubules * The pK' of the ammonia system is 9.0, and the ammonia system is titrated only the from the pH of the urine to pH 7.4, so it contributes very little to the titratable activity.

Answer 883

* Each H⁺ ion that reacts with the buffers contributes to the urinary **titratable acidity** * It is measured by determining the amount of alkali that must be added to the urine to return its pH to 7.4, the pH of the glomerular filtrate * However, the titratable acidity obviously measures only a fraction of the acid secreted, since it does not account of the H₂CO₃ that has been converted to H₂O and CO₂

Answer 884

* Reactions in the renal tubular cells produce NH₄⁺ and HCO₃^-. * NH₄⁺ is in equilibrium with NH₃ and H⁺ in the cells * Because the pK' of this reaction is about 9.0, the ratio of NH₃ to NH₄⁺ at pH 7.0 is about 1:100 * However, NH₃ is lipid-soluble and diffuses across the cell membranes down its concentration gradient into the interstitial fluid and tubular urine * In the urine, it reacts with H⁺ to form NH₄⁺, and the NH₄⁺ remains trapped in the urine

Answer 885

* The principal reactions producing NH₄⁺ in cells is conversion of glutamine to glutamate. * This reaction is catalysed by the enzyme **glutaminase**, which is abundant in renal tubular cells. * **Glutamic dehydrogenase catalyses the conversion of glutamate to α-ketoglutarate, with the production of more NH₄⁺ * Subsequent metabolism of α-ketoglutarate utilises 2H⁺, freeing 2HCO_-⁺

Answer 886

* In chronic acidosis, the amount of NH₄⁺ excreted at any given urine pH also increases, because more NH₃ enters the tubular urine. * The effect of this **adaptation** of NH₃ secretion, the cause of which in unsettled, is further removal of H⁺ from the tubular fluid and consequently a further enhancement of H⁺ secretion but the renal tubules and excretion in the urine.

Answer 887

* Because the amount of phosphate buffer filtered at the glomerulus cannot be increased, urinary exertion of acid via the phosphate buffer system is limited * The production of NH₄⁺ by the renal tubules is the only way the kidneys can remove even the normal amount, much less an increased amount, of non-volatile acid produced in the body

Answer 888

* In the inner medullary cells of the collecting duct, the main process by which NH₃ is secreted into the urin and then changed to NH₄⁺ is called **non-ionic diffusion**, thereby maintaining the concentration gradient for diffusion of NH₃. * In the proximal tubule, non-ionic diffusion of NH₄⁺ is less important because NH₄⁺ can be secreted into the lumen, often by replacing H⁺ on the Na-H exchanger

Answer 889

* A moderate drop in pH occurs in the proximal tubular fluid but most of the secreted H⁺ has little effect on luminal pH because of the formation of CO₂ and H₂O from H₂CO₃ * In contrast, the distal tubule has less capacity to secrete H⁺, but secretion in this segment has a greater effect on urinary pH

Answer 890

Renal acid secretion is altered by changes in the intracellular PCO₂, K⁺ concentration, carbonic anhydrase level, and adrenocortical hormone concentration

Answer 891

When the PCO₂ is high (**respiratory acidosis**), more intracellular H₂CO₃ is available to buffer the hydroxyl ions and acid secretion is enhance, whereas the reverse is true when the PCO₂ falls

Answer 892

K⁺ depletion enhances acid secretion, apparently because the loss of K⁺ causes intracellular acidosis even though the plasma pH may be elevated * Conversely, K⁺ express in the cells inhibits acid secretion.

Answer 893

* Although the process of bicarb reabsorption does not involve active transport of this ion into the tubular cells, it is proportional to the amount filtered over a relatively wide range * Reabsorption is decreased when the ECF volume is expanded. * When the plasma bicarb concentration is low, all of it that is filtered is reabsorbed * When the plasma concentration is high (26-28mEg/L), it appears in the urine and the urine becomes alkaline * Conversely, when the plasma bicarb level falls below 26mEq/L, the value at which all the secreted H⁺ is being used to reabsorb it, more H⁺ becomes available to combine with other buffer anions * Therefore, the lower the plasma bicarb concentration drops, the more acidic the urine becomes and the greater its NH₄⁺

Answer 894

The pH of blood is the pH of **true plasma** - plasma that has been in equilibrium with red cells - because the red cells contain Hb, which is quantitatively one of the most important blood buffers

Answer 895

* Amino acids are utilised in the liver for gluconeogenesis, leaving NH₄⁺ and HCO₃^- as products from their amino acid carboxyl groups * The NH₄⁺ is incorporated into urea and the protons that are formed are buffered intracellularly by HCO₃^-, so little NH₄⁺ and HCO₃^- escape into the circulation

Answer 896

* Metabolism of sulfur-containing amino acids produces H₂SO₄, and metabolism of phosphorylated amino acids such as phosphoserine produces H₃PO₄ * These strong acids enter the circulation and present a major H⁺ load to the buffers in the ECF.

Answer 897

* In metabolic acidosis, only 15-20% of the load is buffered by the H₂CO₃ system in the ECF, and most of the remainder is buffered in cells * In metabolic alkalosis, about 30-35% of the OH^- load is buffered in cells * In respiratory acidosis and alkalosis, almost all of the buffering is intracellular.

Answer 898

* Bicarb reabsorption in the renal tubules depends not only on the filtered load of bicarb, which is the product of the GFR and the plasma bicarb level, but also on the rate of H⁺ secretion by the renal tubular cells, since bicarb is reabsorbed by exchange for H⁺. * The rate of H⁺ secretion - and hence the rate of bicarb reabsorption - is proportional to the arterial PCO₂, probably because the more CO₂ that is available to form H₂CO₃in the tubular cells, the more H⁺ can be secreted. * Furthermore, when the PCO₂ is high, the interior of most cells becomes more acidic.

Answer 899

* In respiratory acidosis, renal tubular H⁺ secretion is increased, removing H⁺ from the body; even though the plasma bicarb is elevated, bicarb reabsorption is increased, further raising the plasma bicarb. Chloride excretion is increased, and plasma chloride falls as plasma bicarb is increased * Conversely, in respiratory alkalosis, the low pCO₂ hinders renal H⁺ secretion, bicarb reabsorption is depressed, and bicarb is excreted, further reading the already low plasma bicarb, and lowering the pH towards normal.

Answer 900

These sphincters include the upper and lower oesophageal sphincters, the pylorus that retards emptying of the stomach, the ileocecal valve that retains colonic contents (including large numbers of bacteria) in the large intestine, and the inner and outer anal sphincters.

Answer 901

* Immediately adjacent to nutrients in the lumen is a single layer of columnar epithelial cells. This represents the barrier that nutrients must traverse to enter the body * Below the epithelium is a layer of loose connective tissue known as the lamina propria, which in turn is surrounded by concentric layers of smooth muscle, orientated circumferentially and then longitudinally to the axis of the gut (the circular and longitudinal muscle layers, respectively) * The intestine is also amply supplied with blood vessels, nerve endings, and lymphatics, which are all important in its function

Answer 902

* Throughout the small intestine, it is folded up into fingerlike projections called villi. * Between the villi are infolding known as crypts. * The villus epithelial cells are also notable for the extensive microvilli are endowed with a dense glycoalyx (the brush border) tat probably protects the cells to some extent from the effects of digestive enzymes. * Some digestive enzymes are also actually part of the brush border, being membrane-bound proteins. These so-called "brush-border hydrolases" perform the final steps of digestion for specific nutrients

Answer 903

* Stem cells that give rise to both crypt and villus epithelial cells reside toward the base of the crypts and are responsible for completely renewing the epithelium every few days or so. * Indeed, the GI epithelium is one of the most rapidly dividing tissues in the body * Daughter cells undergo several rounds of cell division in the crypts and then migrate out onto the villi, where they are eventually shed and lost in the stool

Answer 904

* Saliva is produced by three pairs of salivary glands (the **parotid, submandibular** and **sublingual** glands) that drain into the oral cavity * It has a number of organic constituents that serve to initiate digestion (particularly of starch, mediated by amylase) and which also protect the oral cavity from bacteria (such as immunoglobulin A and lysozyme) * Saliva also serves to the lubricate the food bolus (aided by mucins) * Secretions of the three glands differ in their relative proportion of proteinaceous and mucinous components, which results from the relative number of serous and mucous salivary acinar cells, respectively.

Answer 905

Saliva is hypotonic compared with plasma and alkaline, the latter feature is important to neutralise any gastric secretions that reflux into the oesophagus

Answer 906

* The salivary gland consists of blind end pieces (acini) that produce the primary secretion containing the organic constituents dissolved in a fluid that is essentially identical in its composition to plasma * The salivary glands are actually extremely active when maximally stimulated, secreting their own weight in saliva every minute. To accomplish this, they are richly endowed with surrounding blood vessels that dilate when salivary secretion is initiated. * The composition of the saliva is then modified as it flow from the acini out into ducts that eventually coalesce and deliver the saliva into the mouth.

Answer 907

* Na⁺ and Cl^- are extracted and K⁺ and bicarbonate are added * Because the ducts are relatively impermeable to water, the loss of NaCl renders the saliva hypotonic, particularly at low secretion rates * As the rate of secretion increases, there is less time for NaCl to be extracted and the tonicity of the saliva rises, but it always stays somewhat hypotonic with respect to plasma.

Answer 908

Overall, the three pairs of salivary glands that drain into the mouth supply 1000-1500mL of saliva per day

Answer 909

* Salivary secretion is almost entirely controlled by neural influences, with the parasympathetic branch of the autonomic nervous supply playing the most prominent role. * Sympathetic input slightly modifies the composition of saliva (particularly by increasing proteinaceous content), but has little influence on volume * Secretion is triggered by reflexes that are stimulated by the physical act of chewing, but is actually initiated even before the meal is taken into the mouth as a result of central triggers that are prompted by thinking about, seeing, or smelling food * Salivary secretion is also prompted by nausea but inhibited by fear or during sleep

Answer 910

* It facilitates swallowing, keeps the mouth moist, serves as a solvent for the molecules that stimulate the taste buds, aids speech by facilitating movement of the lips and tongue, and keeps the mouth and teeth clean * The saliva also has some antibacterial action, and patients with deficient salivation (**xerostomia**) have a higher than normal incidence of dental caries * The buffers in saliva help maintain the oral pH at about 7.0

Answer 911

* The gastric mucosa contains many deep glands. * In the cardia and pyloric region, the glands secrete mucus. * In the body of the stomach, including the fundus, the glands also contain **parietal (oxyntic) cells**, which secrete hydrochloric acid and intrinsic factors, and **chief (zymogen, peptic) cells**, which secrete pepsinogens

Answer 912

* The hydrochloric acid, intrinsic factors, and pepsinogens mix with mucus secreted by the cells in the neck of the glands. * Several of the glands open onto a common chamber (**gastric pit**) that opens in turn onto the surface of the mucosa * Mucus is also secreted along with bicarbonate by mucus cells on the surface of the epithelium between glands

Answer 913

* Like salivary secretion, the stomach readies itself to receive the meal before it is actually taken in, during the so-called cephalic phase that can be influenced by food preferences * Subsequently, there is a gastric phase of secretion that is quantitatively the most significant, and finally an intestinal phase once the meal has left the stomach. * Each phase is closely regulated by both local and distant triggers

Answer 914

* The gastric secretions arise from glands in the wall of the stomach that drain into its lumen, and also from the surface cells that secrete primary mucus and bicarbonate to protect the stomach from digesting itself, as well as substances known as trefoil peptides that stabilise the mucus-bicarbonate layer * The **parietal cells**, secrete **hydrochloric acid** and **intrinsic factor**. The acid serves to sterilise the meal and also to begin the hydrolysis of dietary macromolecules. Intrinsic factor is important for the later absorption of vitamin B₁₂ or cobalamin. * The **chief cells**, produce **pepsinogens** and **gastric lipase** . Pepsinogen is the precursor of pepsin, which initiates protein digestion. Lipase similarly begins the digestion of dietary fats.

Answer 915

* **Gastrin** is a hormone that is released by G cells in the antrum of the stomach both in response to a specific neurotransmitter released from enteric nerve endings, known as **gastrin-releasing peptide** (GRP) or bombesin, and also in response to the presence of oligopeptides in the gastric lumen, * Gastrin is then carried through the bloodstream to the fundic glands, where it binds to receptors not only on parietal (and likely, chief cells) to activate secretion, but also on so-called enterochromaffin-like cells (ECL cells) that are located in the gland and release histamine.

Answer 916

* **Gastrin** is released and triggers parietal and chief called * **Histamine** is also a tigger of parietal cell secretion, via binding to H₂-receptors. * Parietal and chief cells can also be stimulated by acetylcholine, released from enteric nerve endings in the fundus

Answer 917

* Gastric secretion that occurs during the cephalic phase is defined as being activated predominantly by vagal input that originates from the brain region known as the dorsal vagal complex, which coordinates input from higher centres. * Vagal outflow to the stomach then releases gastrin releasing peptide (GRP) and acetylcholine, thereby initiating secretory function * Before the meal enters the stomach, there are few additional triggers from the dorsal vagal complex, and thus the amount of secretion is limited.

Answer 918

Once the meal is swallowed, meal constituents trigger substantial release of gastrin and the physical presence of the meal also distends the stomach and activates stretch receptors, which provoke a "vago-vagal" as well as local reflexes that further amplify secretion during the gastric phase.

Answer 919

The presence of the meal also buffers gastric acidity that would otherwise serve as a feedback inhibitor signal to shut off secretion secondary to the release of somatostatin, which inhibits both G and ECL cells as well as secretion by parietal cells themselves.

Answer 920

* The cells are packed with mitochondria that supply energy to drive the apical H⁺, K⁺-ATPase, or proton pump, that moves H⁺ ions out of the parietal cell against a concentration gradient of more than a million-fold. * The resting cell has intracellular canaliculi (IC), which open on the apical membrane of the cell, and many tubulovesicular structures (TV) in the cytoplasm. * When the cell is activated, the TVs fuse with the cell membrane and microvilli (MV) project into the canaliculi, so the area of cell membrane in contact with gastric lumen is greatly increased.

Answer 921

* At rest, the proton pumps are sequestered within the parietal cell in a series of membrane compartments known as tubulovesicles. * When the parietal cell begins to secrete, on the other hand, these vesicles fuse with invaginations of the apical membrane, known as canaliculi * Thereby, substantially amplifying the apical membrane area and positioning the proton pumps to begin acid secretion.

Answer 922

* The apical membrane contains the proton pumps for acid secretion * It also contains potassium channels, which supply the K⁺ ions to be exchanged from H⁺ and Cl^- that supply counterion for HCl. * The secretion of protons is also accompanied by the release of equivalent numbers of bicarbonate ions into the bloodstream, which are later used to neutralise gastric acidity once its function is complete.

Answer 923

* Gastrin and acetylcholine promote secretion by elevating cytosolic free calcium concentrations, whereas histamine increases intracellular cAMP. * It is important to be aware that the two distinct pathways for activation are synergistic, with a greater than additive effect on secretion rates when histamine plus gastrin or acetylcholine, or all three, are present simultaneously. * The physiologic significant of this synergism is that high rates of secretion can be stimulated with relatively small changes in availability of each of the stimuli. * Synergism is also therapeutically significant because secretion can be markedly inhibited by blocking the action of only one of the triggers (mostly commonly histamine with H₂-antagonists)

Answer 924

* Gastric secretion adds about 2.5L/day to the intestinal contents. * However, despite their substantial volume and fine control, gastric secretions are dispensable for the full digestion and absorption of a meal, with the exception of cobalamin absorption. * Digestive and absorptive capacities are markedly in excess of normal requirements.

Answer 925

* The pancreatic juice contains enzymes that are of major importance in digestion. For example: trypsin, chymotrypsin, elastase, carboxypeptidase A and B, colipase, pancreatic lipase, phospholipase A2, colesteryl ester hydrolase, ribonuclease deoxyribonuclease. * Its secretion is controlled in part by a reflex mechanism and in part by the gastrointestinal hormones secretin and cholecystokinin

Answer 926

* Granules containing the digestive enzymes (**zymogen granules**) are formed in the cell and discharged by exocytosis from the apexes of the cells into the lumens of the pancreatic ducts. * The small ducts radicals coalesce into a single duct (pancreatic duct of Wirsung), which usually joins the bile duct to form the ampulla of the bile duct (also known as the ampulla of Vater)

Answer 927

* The ampulla opens through the duodenal papilla, and its orifice is encircled by the sphincter of Oddi * Some individuals have an accessory pancreatic duct (duct of Santorini) that enters the duodenum more proximally.

Answer 928

* The pancreatic juice is alkaline and has a high bicarbonate content (approx 113mEq/L vs 24mEq/L in plasma) * About 1500mL of pancreatic juice is secreted per day * Bile and intestinal juices are also neutral and alkaline, and these three secretions neutralise the gastric acid, raising the pH of the duodenal contents to 6.0-7.0. * By the time the chyme reaches the jejunum, its pH is nearly neutral, but the intestinal contents are rarely alkaline

Answer 929

* Most of these are only activated when they reach the intestinal lumen. * The enzymes are activated following proteolytic cleavage by trypsin, itself a pancreatic protease that is released as an inactive precursor (trypsinogen) * The potential danger of the release into the pancreas of a small amount of trypsin is apparent; the resulting chain reaction would produce active enzymes that could digest the pancreas. It is therefore not surprising that the pancreas also normally secretes a trypsin inhibitor

Answer 930

* This enzyme splits a fatty acid off phosphatidylcholine (PC), forming lyso-PC. * Lyso-PC damages cell membranes. * In acute pancreatitis, phospholipase A₂, is activated prematurely in the pancreatic ducts, with the formation of lyso-PC from the PC that is a normal constituent of bile. This causes disruption of pancreatic tissue and necrosis of surrounding fat.

Answer 931

* Small amounts of pancreatic digestive enzymes normally leak into the circulation, but in acute pancreatitis, the circulating levels of the digestive enzymes rise markedly. * Measurement of the plasma amylase or lipase concentration is therefore of value in diagnosing the disease

Answer 932

* Secretin acts on the pancreatic ducts to cause copious secretion of a very alkaline pancreatic juice that is rich in bicarbonate and poor in enzyme. * The effect on duct cells is due to an increase in intracellular cAMP. * Secretin also stimulates bile secretion * Cholecystokinin acts on acinar cells to cause the release of zymogen granules and production of pancreatic juice rich in enzymes but low in volume. Its effect is mediated by phospholipase C.

Answer 933

As the volume of the pancreatic secretion increases, its Cl^- concentrations falls and its bicarb concentration increases.

Answer 934

The magnitude of the exchange is inversely proportional to the rate of flow

Answer 935

* Like cholecystokinin, acetylcholine acts on acinar cells via phospholipase C to cause discharge of zymogen granules, and stimulation of the vagi causes secretion of a small amount of pancreatic juice rich in enzymes. * There is evidence for vaguely mediated, conditioned reflex secretion of pancreatic juice in response to the sight or smell of food

Answer 936

* The bile acids contained therein are important in the digestion and absorption of fats * In addition, bile serves as a critical excretory fluid by which the body disposes of lipid soluble end products of metabolism as well as lipid soluble xenobiotics. * Bile is also the only route by which the body can dispose of cholesterol - either in its native form, or following conversion to bile acids.

Answer 937

* Bile is made up of the bile acids, bile pigments, and other substances dissolved in an alkaline electrolyte solution that resembles pancreatic juice * About 500mL is secreted per day

Answer 938

Some of the components of the bile are reabsorbed in the intestine and then excreted again by the liver - this is the **enterohepatic circulation**

Answer 939

The glucuronides of the bile pigments, bilirubin and biliverdin, are responsible for the golden yellow colour

Answer 940

* They are synthesised from cholesterol and secreted into the bile conjugated to glycine or taurine, a derivative of cysteine. * The two principal (**primary**) bile acids formed in the liver are **cholic acid** and **chenodeoxycholic acid**. * In the colon, bacteria covert child acid to **deoxycholic acid** and chenodeoxycholic acid to **lithocholic acid** * In addition, small quantities of **ursodeoxycholic acid** are formed from chenodeoxycholic acid. * Because they are formed by bacterial action, deoxycholic, lithocholic and ursodeoxycholic acids are called secondary bile acids.

Answer 941

They reduce surface tension and, in conjunction with phospholipids and monoglycerides, are responsible for the emulsification of fat preparatory to its digestion and absorption in the small intestine.

Answer 942

* They have both hydrophilic and hydrophobic domains; one surface of the molecule is hydrophilic because the polar peptide bond and the carboxyl and hydroxyl groups are on that surface, whereas the other surface is hydrophobic. * Therefore, the bile acids tend to form cylindrical disks called **micelles**. Their hydrophilic portions face out and their hydrophobic portions face in

Answer 943

Above a certain concentration, called the **critical micelle concentration**, all bile salts added to a solution form micelles.

Answer 944

* 90-95% of the bile acids are absorbed from the small intestine. Once they are deconjugated, they can be absorbed by nonionic diffusion, but most are absorbed in their conjugated forms from the terminal ileum by an extremely efficient Na⁺-bile salt co-transport system (ABST) whose activity is secondarily driven by the low intracellular sodium concentration established by the basolateral Na⁺, K⁺, ATPase. * The remaining 5-10% of the bile salts enter the colon and are converted to the salts of deoxycholic acid and lithocholic acid. Lithocholate is relatively insoluble and is mostly excreted in the stools; only 1% is absorbed. However, deoxycholate is absorbed

Answer 945

* The normal rate of bile acid synthesis is 0.2-0.4g/day * The total bile acid pool of approximately 3.5g recycles repeatedly via the enterohepatic circulation * It has been calculated that 4th entire pool recycles twice per meal and 6-8 times per day.

Answer 946

* Water moves passively into and out of the gastrointestinal lumen, driven by electrochemical gradients established by the active transport of ions and other solutes * In the period after a meal, much of the fluid reuptake is driven by the coupled transport of nutrients, such as glucose, its sodium ions. * In the period between meals, absorptive mechanisms centre exclusively around electrolytes. * In both cases, secretory fluxes of fluid are largely driven by the active transport of chloride ions into the lumen, although absorption still predominates overall.

Answer 947

* The intestines are presented each day with about 2000mL of ingested fluid plus 7000mL of secretions from the mucosa of the gastrointestinal tract and associated glands. * 90% of this fluid is reabsorbed, with a daily fluid loss of only 200mL in the stools/

Answer 948

* In the small intestine, secondary active transport of Na⁺ is important in bringing about absorption of glucose, some amino acids, and other substances such as bile acids. * Conversely, the presence of glucose in the intestinal lumen facilitates the reabsorption of Na⁺.

Answer 949

* In the period between meals, when nutrients are not present, sodium and chloride are absorbed together from the intestinal lumen by the coupled activity of a sodium/hydrogen exchanger (NHE) and chloride/bicarbonate exchanger in the apical membrane, in a so-called electroneutral mechanism * Water then follows to maintain an osmotic balance.

Answer 950

* In the colon, an additional electrogenic mechanism for sodium absorption is expressed, particularly in the distal colon. * In this mechanism, sodium enters across the apical membrane via an ENaC (epithelial sodium) channel that is identical to that expressed in the distal tubule of the kidney * This underpins the ability of the colon to desiccate the stool and ensure that only a small potion of the fluid load used daily in the digestion and absorption of meals is lost from the body. * Following a low-salt diet, increased expression of ENaC in response to aldosterone increases the ability to reclaim sodium from the stool

Answer 951

* Cl^- normally enters enterocytes from the interstitial fluid via Na⁺-K⁺-2Cl^- cotransporters in their basolateral membranes. * The cystic fibrosis transmembrane conductance regulator (CFTR) channel that is defective in cystic fibrosis is quantitatively most important, and is activated by protein kinase A and hence by cAMP

Answer 952

* The osmolality of the duodenal contents may be hypertonic or hypotonic, depending on the meal ingested, but by the time the meal enters the jejunum, its osmolality is close to that of plasma * This osmolality is maintained throughout the rest of the small intestine; the osmotically active particles produced by digestion are removed by absorption, and water moves passively out of the gut along the osmotic gradient thus generated. * In the colon, Na⁺ is pumped out and water moves passively with it, again along the osmotic gradient.

Answer 953

Saline cathartics such as magnesium sulfate are poorly absorbed salts that retain their osmotic equivalent of water in the intestine, thus increasing intestinal volume and consequently exerting a laxative effect

Answer 954

* K⁺ channels are present in the luminal as well as the basolateral membrane of the enterocytes of the colon, so K⁺ is secreted into the colon * In addition, K⁺ moves passively down its electrochemical gradient. * The accumulation of K ⁺in the is partially offset by H⁺-K⁺ ATPase in the luminal membrane of cells in the distal colon, with resulting active transport of K⁺ into the cells * Nevertheless, loss of ileal or colonic fluids in chronic diarrhoea can lead to severe hypokalaemia

Answer 955

* Aldosterone secretion is increased and more K⁺ enters the colonic lumen. * This is due in part to the appearance of more Na⁺, K⁺, ATPase pumps in the basolateral membranes of the cells, with a consequent increase in intracellular K⁺ and K⁺ diffusion across the luminal membranes of the cells, with a consequent increase in intracellular K⁺ and K⁺ diffusion across the luminal membranes of the cells.

Answer 956

1) First, **endocrine** regulation is mediated by the release of hormones by triggers associated with the meal. These hormone travel through the bloodstream to change the activity of a distant segment of the gastrointestinal tract, an organ draining into it (the pancreas), or both. 2) Second, some similar mediators are not sufficiently stable to persist in the bloodstream, but instead alter the function of cells in the local area where they are released, in a **paracrine** fashion 3) Finally, the intestinal system is endowed with extensive neural connections. There include connections to the CNS (**extrinsic innervation**), but also the activity of a largely autonomous **enteric nervous system** that comprises both sensory and secretomotor neurons. The enteric nervous system integrated central input to the gut but can also regulate gut function independently in response to change in the luminal environment.

Answer 957

* The **gastrin** family, the primary members of which are gastrin and cholecystokinin * The **secretin** family, the primary members of which are secretin, glucagon, vasoactive intestinal peptide (VIP; actually a neurotransmitter, or neuroendocrine) and gastric inhibitor polypeptide (also known as glucose-dependent insulinotropic peptide or GIP).

Answer 958

* More than 15 types of hormone-secreting **enteroendocrine cells** have been identified in the mucosa of the stomach, small intestine, and colon * Many of these secrete only one hormone and are identified by letters (G cells, S cell, etc) * Others manufacture serotonin or histamine and are called **enterochromaffin** or **ECL cells**, respectively

Answer 959

* Gastrin is produced by cells called G cells in the antral portion of the gastric mucosa. * G cells are flask-shaped, with a broad base containing many gastrin granules and a narrow apex that reaches the mucosal surface * Microvilli project from the apical end into the lumen * Receptors mediating gastrin responses to changes in gastric contents are present on the microvilli

Answer 960

* The precursor for gastrin, preprogastrin, is processed into fragments of various sizes. * Three main fragments contain 34, 17, and 14 amino acid residues. All have the same carboxyl terminal configuration. These forms are also known as G34, G17, and G14 gastrins, respectively. * Another form is the carboxyl terminal tetra peptide, and there is also a large form that is extended at the amino terminal and contains more than 45 amino acid residues * One form of derivatisation is sulfation of the tyrosine that is the sixth amino acid residue from the carboxyl terminal. * Approximately equal amounts of non-sulfated and sulphated forms are present in blood and tissues, and they are equally active. * Another derivatisation is admiration of the carboxyl terminal phenylalanine, which likely enhances the peptide's stability in the plasma by rendering it resistant to carboxypeptidases.

Answer 961

* G17 is the principal form with respect to gastric acid secretion. * The carboxyl terminal tetrapeptide has all the activities of gastrin but only 10% of the potency of G17. * G14 and G17 have half-lives of 2-3 minutes in the circulation, whereas G34 has a half-life of 15 minutes. * Gastrins are inactivated primarily in the kidney and small intestine

Answer 962

* Stimulation of gastric acid and pepsin secretion * Stimulation of the growth of the mucosa of the stomach and small and large intestines (**trophic action**)

Answer 963

**Luminal** Peptides and amino acids Distention **Neural** Increased vagal discharge via GRP (gastrin releasing polypeptide) **Bloodborne** Calcium Adrenaline

Answer 964

**Luminal** Acid Somatostatin **Bloodborne** Secretin, GIP, VIP, glucagon, calcitonin

Answer 965

The transmitter secreted by the postganglionic vagal fibers that innervate the G cells is gastrin-releasing polypeptide (GRP) rather than acetylcholine.

Answer 966

* Gastrin secretion is increased by the presence of the products of protein digestion in the stomach, particularly amino acids, which act directly on the G cells. * Phenylalanine and tryptophan are particularly effective.

Answer 967

* Gastrin acts via a receptor CCK-B that is related to the primary receptor (CCK-A) for cholecystokinin. * This likely reflects that structural similarity of the two hormones, and may result in some overlapping actions if excessive quantities of either hormone are present (eg, in the case of a gastrin-secreting tumour, or gastrinoma)

Answer 968

* Acid in the antrum inhibits gastrin secretion, partly by the direct action on G cells and partly by release of somatostatin, a relatively potent inhibitor of gastrin secretion. * The effect of acid is the basis of a negative feedback loop regulating gastrin secretion. * Increased secretion of the hormone increases acid secretion, but the acid then feeds back to inhibit further secretion. * In conditions such as pernicious anaemia in which the acid-secreting cells of the stomach are damaged, gastrin secretion is chronically elevated.

Answer 969

* CCK is secreted by endocrine cells known as I cells in the mucosa of the upper small intestine * It has a plethora of actions in the GI system, but the most important appears to be the stimulation of pancreatic enzyme secretion; the contraction of the gallbladder (the actions for which it was names); and relaxation of the sphincter of Oddi, which allows both bile and pancreatic juice to flow into the intestinal lumen

Answer 970

* Prepro-CKK is also processed into many fragments * A large CCK contains 58 amino acid residues (CCK 58) * In addition, there are CCK peptides that contain 39 amino acid residues (CCK 39) and 33 amino acid residues (CCK 33), several forms that contain 12 (CCK 12) or slightly more amino acid residues and a form that contains eight amino acid residues (CCK 8) * All these forms have the same five amino acids at the carboxyl terminal as gastrin. The carboxyl terminal tetrapeptide (CCK4) also exists in tissues. The carboxyl terminal is amidated, and the tyrosine that is the seventh amino acid residue from the carboxyl terminal is sulphated. * Unlike gastrin, the non-sulfated form of CCK has not been found in tissues * The half-life of circulating CCK is about 5 minutes.

Answer 971

* In addition to its secretion by I cells, CCK is found in nerves in the distal ileum and colon. * It is also found in neurons in the brain, especially the cerebral cortex, and in nerves in many parts of the body. * In the brain, it may be involved in the regulation of food intake, and it appears to be related to the production of anxiety and analgesia

Answer 972

* CCK augments the action of secretin in producing secretion of an alkaline pancreatic juice * It also inhibits gastric emptying * It exerts a trophic effect on the pancreas, * Increases the synthesis of enterokinase * May enhance the motility of the small intestine and colon. * There is some evidence that, along with secretin, it augments the contraction of the pyloric sphincter, thus preventing the reflux of duodenal contents into the stomach

Answer 973

* CCK-A receptors are primarily located in the periphery, whereas both CCK-A and CCK-B (gastrin) receptors are found in the brain. * Both activate phospholipase C, causing increased production of IP₃ and DAG (diacylglycerol).

Answer 974

* The secretion of CCK is increased by contact of the intestinal mucosa with the products of digestion, particularly peptides and amino acids, and also by the presence in the duodenum of fatty acids containing more than 10 carbon atoms. * There are also two protein releasing factors that activate CCK secretion, known as CCK-releasing peptide and monitor peptide, which derive from the intestinal mucosa and pancreas, respectively * Because the bile and pancreatic juice that enter the duodenum in response to CCK enhance the digestion of protein and fat, and the products of this digestion stimulate further CCK secretion, a positive feedback operates. * However, the positive feedback is terminated when the products of digestion move on to the lower portions of the GI tract and also because CCK-releasing peptide and monitoring peptide are degraded by proteolytic enzymes once these are no longer occupied in digesting dietary proteins.

Answer 975

* Secretin is secreted by S cells that are located deep in the glands of the mucosa of the upper portion of the small intestine. * The structure of secretin is different from that of CCK and gastrin, but very similar to that of GIP, glucagon and VIP. * Only one form of secretin has been isolated, and any fragments of the molecules that have been tested to date are inactive. * Its half-life is about 5 minutes.

Answer 976

* Secretin increases the secretion of bicarbonate by the duct cells of the pancreas and biliary tract. * It thus causes the secretion of a watery, alkaline pancreatic juice * Its action on pancreatic duct cells is mediated via cAMP * It also augments the action of CCK in producing pancreatic secretion of digestive enzymes. * It decreases gastric acid secretion and may cause contraction of the pyloric sphincter

Answer 977

* The secretion of secretin is increased by the products of protein digestion and by acid bathing the mucosa of the upper small intestine. * The release of secretin by acid is another example of feedback control: secretin causes alkaline pancreatic juice to flood into the duodenum, neutralising the acid from the stomach and thus inhibiting further secretion of the hormone

Answer 978

* GIP contains 42 amino acid residues and is produced by K cells in the mucosa of the duodenum and jejunum. * Its secretion is stimulated by glucose and fat in the duodenum, and because in large doses it inhibits gastric secretion and motility, it was named gastric inhibitory peptide. However, it now appears that it does not have significant gastric inhibiting activity when administered in smaller amounts comparable to those seen after a meal * In the meantime, it was found that GIP stimulates insulin secretion. Gastrin, CCK, secretin, and glucagon also have this effect, but GIP is the only one of these that stimulates insulin secretion when administered at blood levels comparable to those produced by oral glucose. For this reason, it is often called **glucose-dependent insulinotropic peptide**.

Answer 979

* It is found in nerves in the GI tract and thus is not itself a hormone, despite its similarities to secretin. * VIP is, however, found in blood, in which is has a half-life of about 2 minutes * In the intestine, it markedly stimulates intestinal secretion of electrolytes and hence of water. * Its other actions include relaxation of intestinal smooth muscle, including sphincters; dilation of peripheral blood vessels, and inhibition of gastric acid secretion. * It is also found in the brain and many autonomic nerves, where it often occurs in the same neurons as acetylcholine. It potentiates the action of acetylcholine in salivary glands. However, VIP and acetylcholine do not exist in neurons that innervate other parts of the GI tract.

Answer 980

* Motilin is secreted by enterochromaffin cells and Mo cells in the stomach, small intestine, and colon. * It acts on G-protein-coupled receptors on enteric neurons in the duodenum and colon and produces contract. of smooth muscle in the stomach and intestines in the period between meals

Answer 981

* Somatostatin, the growth hormone-inhibiting hormone originally isolated from the hypothalamus, is secreted as a paracrine by D cells in the pancreatic islets and by similar D cells in the GI mucosa. * It exists in tissues in two forms, somatostatin 14 and somatostatin 28, and both are secreted. * Somatostatin inhibits the secretion of gastrin, VIP, GIP, section and motilin * Its secretion is stimulated by acid in the lumen, and it probably acts in a paracrine fashion to mediate the inhibition of gastrin secretion produced by acid. * It also inhibits pancreatic exocrine secretion; gastric acid secretion and motility, gallbladder contraction; and the absorption of glucose, amino acids, and triglycerides

Answer 982

* It inhibits gastric acid secretion and motility and is a good candidate to be the gastric inhibitory peptide. * Its release from the jejunum is stimulated by fat

Answer 983

* Ghrelin is secreted primarily by the stomach and appears to play an important role in the central control of food intake * It also stimulates growth hormone secretion by acting directly on receptors in the pituitary

Answer 984

* Substance P is found in endocrine and nerve cells in the GI tract and may enter the circulation * It increases the motility of the small intestine.

Answer 985

The neurotransmitter GRP is present in the vagal nerve endings that terminate on G cells and is the neurotransmitter producing vaguely mediated increases in gastrin secretion

Answer 986

* Guanylin is a gastrointestinal polypeptide that binds to guanylyl cyclase. * It is secreted by cells of the intestinal mucosa * Stimulation of guanylyl cyclase increases the concentration of intracellular cGMP and this in turn causes increased secretion of Cl^- into the intestinal lumen. * Guanylin appears to act predominantly in a paracrine fashion, and it is produced in cells from the pylorus to the rectum. * Guanylin receptors are also found in the kidneys, the liver, and the female reproductive tract, and guanylin may act in an endocrine fashion to regulate fluid movement in these tissues as well, and particularly to integrate the actions of the intestine and kidneys

Answer 987

* The **myenteric plexus** (Auerbach plexus), between the outer longitudinal and middle circular muscle layers * The **submucous plexus** (Meissner plexus), between the middle circular layer and the mucosa * Collectively, these neurons constitute the generic nervous system.

Answer 988

* It is connected to the CNS by parasympathetic and sympathetic fibers * But it can function autonomously without these connections.

Answer 989

* The myenteric plexus innervates the longitudinal and circular smooth muscle layers and is concerned primarily with motor control * Whereas the submucous plexus innervates the glandular epithelium, intestinal endocrine cells, and submucosal blood vessels and is primarily involved in the control of intestinal secretion.

Answer 990

* The neurotransmitters in the system include acetylcholine, the amines noradrenaline and serotonin, the amino acid GABA, the purine ATP, the gases NO and CO, and many different peptides and polypeptides * Some of these peptides also act in a paracrine fashion, and some enter the bloodstream, becoming hormones

Answer 991

* Parasympathetic cholinergic activity generally increasing the activity of intestinal smooth muscle * Sympathetic noradrenergic activity generally decreasing it while causing sphincters to contract

Answer 992

* The preganglionic parasympathetic fibers consist of about 2000 vagal efferents and other efferents in the sacral nerves. They generally end on cholinergic nerve cells of the myenteric and submucous plexus. * The sympathetic fibers are postganglionic, but many of them end on postganglionic cholinergic neurons, where the noradrenaline they secrete inhibits acetylcholine secretion by activating α₂ presynaptic receptors. Other sympathetic fibers appear to end directly on intestinal smooth muscle cells

Answer 993

* They have extrinsic noradrenergic innervation and intrinsic innervation by fibers of the enteric nervous system * VIP and NO are among the mediators in the intrinsic innervation, which seems, among other things, to be responsible for the increase in local blood flow (**hyperaemia**) that accompanies digestion of food.

Answer 994

* The intestinal mucosa contains more lymphocytes than are found in the circulation, as well as large numbers of inflammatory cells that are placed to rapidly defend the mucosa if epithelial defences are breached * It is likely that immune cells, and their products, also impact the physiologic function of the epithelium, endocrine cells, nerves and smooth muscle, particularly at times of infection and if inappropriate immune responses are perpetuated, such as in IBD

Answer 995

* The blood flow to the stomach, intestines, pancreas and liver is arranged in a series of parallel circuits, with all the blood from the intestines and pancreas draining via the portal vein to the liver. * The blood from the intestines, pancreas, and spleen drains via the hepatic portal vein to the liver and from the liver via the hepatic veins to the inferior vena cava.

Answer 996

* The viscera and the liver receive about 30% of the cardiac output via the celiac, superior mesenteric and inferior mesenteric arteries. * The liver receives about 1300mL/min from the portal vein and 500mL/min from the hepatic artery during fasting, and the portal supply increases still further after meals

Answer 997

* The principal dietary carbohydrates are **polysaccharides, disaccharides, and monosaccharides**. * **Starches** (glucose polymers) and their derivatives are the only **polysaccharides** that are digested to any degree in the human GI tract by human enzymes * Amylopectin, which typically constitutes around 75% of dietary starch, is a branched molecule, whereas amylose is a straight chain with only 1:4α linkages * The **disaccharides lactose** and **sucrose** are also ingested along with **monosaccharides fructose and glucose**.

Answer 998

* In the mouth, starch is attacked by salivary α-amylase. The optimum pH for this enzyme is 6.7. However it remains partially active even once it moves into the stomach, despite the acidic gastric juice, because the active site is protected in the presence of substrate to some degree * In the small intestine, both the salivary and pancreatic α-amylase also act on the ingested polysaccharides * Both the salivary and pancreatic α-amylase hydrolyse internal 1:4α linkages but spare 1:6α linkages and terminal 1:4α linkages. * Consequently, the end products of α-amylase digestion are oligosaccharides: the disaccharide **maltose**; the trisaccharide **maltotriose**; and **α-limit dextrins**, polymers of glucose containing an average of about eight glucose molecules with 1:6α linkages.

Answer 999

* Some of these enzymes have more than one substrate. * **Isomaltase** is mainly responsible for the hydrolysis of 1:6α linkages. Along with **maltase** and **sucrase**, it also breaks down maltotriose and maltose * Sucrase and isomaltase are initially synthesised as a single glycoprotein chain that is inserted into the brush border membrane. It is then hydrolysed by pancreatic proteases into sucrase and isomaltase subunits.

Answer 1000

* Sucrase hydrolyses sucrose into a molecule of glucose and a molecule of fructose. * Lactase hydrolyses lactose to glucose and galactose

Answer 1001

* It may cause diarrhoea, bloating and flatulence after ingestion of sugar * The diarrhoea is due to the increased number of osmotically active oligosaccharide molecules that remain in the intestinal lumen, causing the volume of the intestinal contents to increase.

Answer 1002

* In the colon, bacteria break down some of the oligosaccharides, further increasing the number of osmotically active particles * The bloating and flatulence are due to the production of gas (CO₂ and H₂) from disaccharide residues in the lower small intestine and colon.

Answer 1003

* Hexoses are rapidly absorbed across the wall of the small intestine * Essentially all the hexoses are removed before the remains of a meal reach the terminal part of the ileum * The sugar molecules pass from the mucosal cells to the blood in the capillaries draining into the portal vein

Answer 1004

* The transport of glucose and galactose depends on Na⁺ in the intestinal lumen; a high concentration of Na⁺ on the mucosal surface of the cells facilitates sugar influx into the epithelial cells while a low concentration inhibits sugar influx into the epithelial cells * This is because these sugars and Na⁺ share the same **cotransporter**, or **symport**, the **sodium-dependent glucose transporter** (SGLT)

Answer 1005

* The members of this family of transporters, SGLT-1 and SGLT-2, resemble the glucose transporters (GLUTs) responsible for facilitated diffusion in that they cross the cell membrane 12 times and have their -COOH and -NH⁺terminals on the cytoplasmic side of the membrane. * SLGT-1 is responsible for uptake of dietary glucose from the gut * SGLT-2 is responsible for glucose transport out of the renal tubule.

Answer 1006

* Because the intracellular N⁺ concentration is low in intestinal cells, Na⁺ moves into the cell along its concentration gradient. * Glucose moves with the Na⁺ and is released in the cell * The Na⁺ is transported into the lateral intercellular spaces * The glucose is transported by GLUT2 into the interstitium and thence the capillaries.

Answer 1007

* The energy for glucose transport is provided indirectly by the active transport of Na⁺ out of the cell. * This maintains the concentration gradient across the luminal border of the cell, so that more Na⁺ and consequently more glucose enter.

Answer 1008

* Its absorption is independent of Na⁺ or the transport of glucose and galactose * It is transported instead by facilitated diffusion from the intestinal lumen into the enterocytes by GLUT5 and out of the enterocytes into the interstitium by GLUT2. * Some fructose is converted to glucose in the mucosal cells

Answer 1009

* Insulin has little effect on intestinal transport of sugars. * In this respect, intestinal absorption resembles glucose reabsorption in the proximal convoluted tubules of the kidneys; neither process requires phosphorylation, and both are essentially normal in diabetes but are depressed by the drug phorizin

Answer 1010

The maximal rate of glucose absorption from the intestine is about 120g/.hour

Answer 1011

* Pepsins cleave some of the peptide linkages * Pepsins are secreted in the form of inactive precursors (**proenzymes**) and activated in the GI tract. * The pepsin precursors are called pepsinogens and are activated by gastric acid

Answer 1012

* Pepsinogen I and pepsinogen II * **Pepsinogen I** is found only in acid-secreting regions * **Pepsinogen II** is also found in the pyloric region * Maximal acid secretion correlated with pepsinogen I levels

Answer 1013

* Pepsins hydrolyse the bonds between aromatic amino acids such as phenylalanine or tyrosine and a second amino acid, so the products of peptic digestion are polypeptides of very diverse sizes. * Because pepsins have a pH optimum of 1.6-3.2, their action is terminated when the gastric contents are mixed with the alkaline pancreatic juice in the duodenum and jejunum. * The pH of intestinal contents in the duodenal bulb is 3.0-4.0, but rapidly rises, in the rest of the duodenum it is about 6.5

Answer 1014

* **Trypsin, the chymotrypsins, and elastase** act at interior peptide bones in the peptide molecules and are called **endopeptidases** * The formation of the active endopeptidases from their inactive precursors occurs only when they have reached their site of action, secondary to the action of the brush border hydrolase, **enterokinase** * Trypsinogen is converted to the active enzyme trypsin by **enterokinase** when the pancreatic juice enters the duodenum. * Trypsin converts chymotrypsinogens into chymotrypsins and other proenzymes into active enzymes. * Trypsin can also activate trypsinogen; therefore, once some trypsin is formed, there is an auto-catalytic chain reaction.

Answer 1015

It contains 41% polysaccharide, and this high polysaccharide content apparently prevents it from being digested itself before it can exert its effect

Answer 1016

* The carboxypeptidases of the pancreas are **exopeptidases** that hydrolyse the amino acids at the carboxyl ends of the polypeptides. * Some free amino acids are liberated in the intestinal lumen, but others are liberated at the cell surface by the aminopeptidases, carboxypeptidases, endopeptidases, and dipeptidases in the brush border of the mucosal cells. * Some dipeptides and tripeptides are actively transported into the intestinal cells and hydrolysed by intracellular peptidases, with the amino acids entering the bloodstream. * Thus, the final digestion to amino acids occurs in three locations: the intestinal lumen, the brush border, and the cytoplasm of the mucosal cells.

Answer 1017

* Five of these require Na⁺ and cotransport amino acids and Na⁺ in a fashion similar to the cotransport of Na⁺ and glucose. * Two of these five also require Cl^- * In two systems, transport is independent of Na⁺

Answer 1018

* By a system known as PepT1 (or peptide transporter 1) that requires H⁺ instead of Na⁺. * There is very little absorption of larger peptides. * In the enterocytes, amino acids released from the peptides by intracellular hydrolysis plus the amino acids absorbed from the intestinal lumen and brush border are transported out of the enterocytes along their basolateral borders by at least five transport systems. * From there, they enter the hepatic portal blood

Answer 1019

* Absorption of amino acids is rapid in the duodenum and jejunum. * There is a little absorption in the ileum in health, because the majority of the free amino acids have already been assimilated at that point

Answer 1020

* Approximately 50% from ingested food * 25% from proteins in digestive juices * 25% from desquamated mucosal cells * Only 2-5% of the protein in the small intestine escapes digestion and absorption. * Some of this is eventually digested by bacterial action in the colon * Almost all of the protein in the stools is not of dietary origin but comes from bacteria and cellular debris.

Answer 1021

* The protein antibodies in maternal colostrum are largely secretory immunoglobulins (IgAs), the production of which is increased in the breast in late pregnancy * The cross the mammary epithelium by transcytosis and enter the circulation of the infant from the intestine, providing passive immunity against infections. * Absorption is by endocytosis and subsequent exocytosis

Answer 1022

Foreign proteins that enter the circulation provoke the formation of antibodies, and the antigen-antibody reaction occurring on subsequent entry of more of the same protein may cause allergic symptoms.

Answer 1023

* Absorption of protein antigens, particularly bacterial and viral proteins, takes place in large **microfold cells** or **M cells**, specialised intestinal epithelial cells that overlie aggregated of lymphoid tissue (Peyer patches). * These cells pass the antigens to the lymphoid cells, and lymphocytes are activated * The activated lymphoblasts enter the circulation, but they later return to the intestinal mucosa and other epithelia, where they secrete IgA in response to subsequent exposures to the same antigen. * This **secretory immunity** is an important defence mechanism

Answer 1024

* Nucleic acids are split into nucleotides in the intestine by the pancreatic nucleases, and the nucleotides are split into the nucleosides and phosphoric acid by enzymes that appear to be located on the luminal surfaces of the mucosal cells. * The nucleosides are then split into their constituent sugars and purine and pyrimidine bases. The bases are absorbed by active transport. * Families of equilibrate (ie, passive) and concentrative (ie, secondary active) nucleoside transporters have recently been identified and are expressed on the apical membrane of enterocytes.

Answer 1025

* A lingual lipase is secreted by Ebner glands on the dorsal surface of the tongue in some species, and the stomach also secretes a lipase. * They are of little quantitative significant for lipid digestion other than in the setting of pancreatic insufficiency, but they may generate free fatty acids that signal to most distal parts of the GI tract.

Answer 1026

* This enzyme hydrolyses with 1- and 3- bonds of the triglycerides with relative ease but acts on the 2-bonds at a very low rate, sot eh principal products of its actions are free fatty acids and 2-monoglycerides. * It acts on fats that have been emulsified * Its activity is facilitated when an amphipathic helix that covers the active site like a lid is bent back.

Answer 1027

* **Colipase** is secreted alongside lipase in the pancreatic juice, and when this molecule binds to the -COOH-terminal domain of the pancreatic lipase, opening of the lid is facilitated. * Colipase is secreted in an inactive proform and is activated in the intestinal lumen by trypsin. * Colipase is also critical for the action of lipase because it allows lipase to remain associated with droplets of dietary lipid even in the presence of bile acids

Answer 1028

* Cholesterol esterase represents about 4% of the total protein in pancreatic juice * In adults, pancreatic lipase is 10-60 times more active, but unlike pancreatic lipase, cholesterol esterase catalyses the hydrolysis of cholesterol esters, esters of fat-soluble vitamins, and phospholipids, as well as triglycerides.

Answer 1029

* They are finely emulsified in the small intestine by the detergent action of bile acids, phosphatidylcholine, and monoglycerides. * When the concentration of bile acids in the intestine is high, as it is after contraction of the gallbladder, lipids and bile acids interact spontaneously to form **micelles**. * These cylindrical aggregates take up lipids, and although they lipid concentration varies, they generally contain fatty acids, monoglycerides, and cholesterol in their hydrophobic centres * Micellar formation further solubilises the lipids and provides a mechanism for their transport to the enterocytes. * Thus, the micelles move down their concentration gradient through the unstirred layer to the brush border of the mucosal cells. The lipids diffuse out of the micelles, and a saturated aqueous solution of the lipids is maintained in contact with the brush border of the mucosal cells

Answer 1030

* It is mostly due to lipase deficiency. However, acid inhibits the lipase, and the lack of alkaline secretion from the pancreas also contributes by lowering the pH of the intestine contents * In some cases, hypersecretion of gastric acid can cause steatorrhoea * Another cause is defective reabsorption of bile acids in teh distal ileum

Answer 1031

* Traditionally, lipids were thought to enter the enterocytes by passive diffusion, but some evidence now suggests that carriers are involved. * Inside the cells, the lipids are rapidly esterified, maintaining a favourable concentration gradient from the lumen into the cells. * There are also carriers that export certain lipids back into the lumen, thereby limiting their oral availability.

Answer 1032

* Fatty acids containing less than 10-12 carbon atoms are water-soluble enough that they pass through the enterocyte unmodified and are actively transported into the portal blood. They circulate as free (unesterified) fatty acids. * The fatty acids containing more than 10-12 carbon atoms are too insoluble for this. They are re-esterified to triglycerides in the enterocytes. * In addition, some of the absorbed cholesterol is esterified. The triglycerides and cholesterol esters are then coated with a layer of protein, cholesterol and phospholipid to form chylomicrons. These leave the cell and enter the lymphatics, because they are too large to pass through the junctions between capillary endothelial cells.

Answer 1033

* Most of the triglyceride is formed by the acylation of the absorbed 2-monoglycerides, primarily in the smooth endoplasmic reticulum. * However, some of the triglyceride is formed from glycerophosphate, which in turn is a product of glucose catabolism. Glycerophosphate is also converted into glycerophospholipids that participate in chylomicron formation. * The acylation of glycerophosphate and the formation of lipoproteins occur in the rough endoplasmic reticulum * Carbohydrate moieties are added to the proteins in the Golgi apparatus, and the finished chylomicrons are extruded by exocytosis from the basolateral aspect of the cell

Answer 1034

* Absorption of long-chain fatty acids is greatest in the upper parts of the small intestine, but appreciable amounts are also absorbed in the ileum * On a moderate fat intake, 95% or more of the ingested fat is absorbed.

Answer 1035

* Short-chain fatty acids (SCFAs) that are produced in the colon and absorbed from it * They are weak acids that have a normal concentration of about 80mmol/L in the lumen * About 60% of this total is acetate, 25% propionate, and 5% butyrate * They are formed by the action of colonic bacteria on complex carbohydrates, resistant starches and other components of the dietary fiber, that is, the material that escapes digestion in the upper GI tract and enters the colon.

Answer 1036

* Absorbed SCFAs are metabolised and make a significant contribution to the total caloric intake * In addition, they exert a trophic effect on the colonic epithelial cells; combat inflammation; and are absorbed in part by exchange for H⁺; helping maintain acid-base equilibrium.

Answer 1037

Vitamins are defined as small molecules that play vital roles in bodily biochemical reactions, and which must be obtained from the diet because they cannot be synthesised endogenously

Answer 1038

* The fat soluble vitamins A, D, E and K are ingested as esters and must be digested by cholesterol esterase prior to absorption * These vitamins are also highly insoluble in the gut, and their absorption is therefore entirely dependent on their incorporation into micelles. * Their absorption is deficient if aft absorption is depressed because of lack of pancreatic enzymes or if bile is excluded from the intestine by obstruction of the bile duct.

Answer 1039

Most vitamins are absorbed in the upper small intestine, but vitamin B₁₂ is absorbed in the ileum

Answer 1040

This vitamin binds to intrinsic factor, a protein secreted by the parietal cell of the stomach, and the complex is absorbed across the ileal mucosa

Answer 1041

Vitamin B12 absorption and folate absorption at Na⁺ independent, but all seven of the remaining water-soluble vitamins (thiamin, riboflavin, niacin, pyridoxine, pantothenate, biotin, and ascorbic acid - are absorbed by carriers that are Na⁺ cotransporters

Answer 1042

* In adults the amount of iron lost from the body is relatively small. * The losses are generally unregulated, and total body stores of iron are regulated by changes in the rate at which it is absorbed from the intestine

Answer 1043

* Men lose about 0.6mg/day, largely in the stools * Premenopausal women have a variable, larger loss averaging about twice this value because of the additional iron lost during menstruation * The average daily iron intake in the US and Europe is about 20mg, but the amount absorbed is equal only to the losses. * Thus the amount of iron absorbed is normally about 3-6% of the amount ingested

Answer 1044

* Most of the iron in the diet is in the Ferric (Fe³⁺) form, whereas it is the ferrous (Fe²⁺) form that is absorbed * Fe³⁺ reductase activity is associated with the iron transporter in the brush borders of the enterocytes. * Gastric secretions dissolve the iron and permit it to form soluble complexes with ascorbic acid and other substances that aid its reduction to the Fe²⁺ form.

Answer 1045

* Transport of Fe²⁺ into the enterocytes occurs via divalent metal transporter 1 (DMT1) * Some is stored in ferritin, and the remainder is transported out of the enterocytes by a basolateral transporter names **ferroportin 1** * A protein called **hephaestin (Hp)** is associated with ferroportin 1. It is not a transporter itself, but it facilitates basolateral transport.

Answer 1046

* In the plasma, Fe²⁺ is covered to Fe³⁺ and bound to the iron transport protein **transferrin** * This protein has two iron-binding sites. * Normally, transferrin is about 35% saturated with iron, and the normal plasma iron level is about 130 μg/dL (23 μmol/L) in men and 110 μg/dL (19 μmol/L) in women.

Answer 1047

* Heme binds to an apical transport protein in enterocytes and is carried into the cytoplasm * In the cytoplasm, HO-2, a subtype of heme oxygenase, removes Fe₂₊ from the porphyrin and adds it to the intracellular Fe₂₊ pool

Answer 1048

* Ferritin is present not only in enterocytes, but also in many other cells * Ferritin molecules in lysosomal membranes may aggregate in deposits that contain as much as 50% iron. These deposits are called **hemosiderin**

Answer 1049

* Recent dietary intake of iron * The state of iron stores in the body * The state of erythropoiesis in the bone marrow

Answer 1050

* **CCK** either produced by I cells in the intestine, or released by nerve endings in the brain, inhibits further food intake and thus is defined as **satiety factor** * **Leptin and ghrelin** are peripheral factors that act reciprocally on food intake. Both activate their receptors in the hypothalamus that initiate signalling cascades leading to changes in food intake.

Answer 1051

* Leptin is produced by adipose tissue, and signals the status of the fat stores therein * As adipocytes increase in size, they release greater quantities of leptin and this tends to decrease food intake, in part by increasing the expression of other anorexigenic factors in the hypothalamus such as pro-opiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), neurotensin, and corticotropin-releasing hormone (CRH). * Leptin also stimulates the metabolic rate

Answer 1052

* It is produced mainly by the stomach, as well as other tissues such as the pancreas and adrenal glands in responses to changes in nutritional status - circulating ghrelin levels increase preprandially, then decrease after a meal * It is believed to be involved primary in meal initiation, unlike the longer-term effects of leptin. * It increases synthesis and/or release of central orexin, including neuropeptide Y and cannabinoids, and suppresses the ability to stimulate anorexigenic factors * Loss of the activity of ghrelin may account in part for the effectiveness of gastric bypass procedures for obesity * Its secretion may also be inhibited by leptin, underscoring the reciprocity of these hormones

Answer 1053

* In the body, oxidation is not a one-step, semi explosive reaction but a complex, slow, stepwise process called **catabolism**, which liberates energy in small, usable amount * Energy can be stored in the body in the form of special energy-rich phosphate compounds and in the form of proteins, fats and complex carbohydrates synthesised from simpler molecules. Formation of these substances by processes that take up rather than livery energy is called **anabolism**

Answer 1054

Energy output = external work + energy storage + heat

Answer 1055

* Isotonic muscle contractions perform work at a peak efficiency approximating 50% * Essentially all of the energy of isometric contractions appears as heat, because little or no external work is done

Answer 1056

* Essentially all of the energy of isometric contractions appear as heat, because little or no external work is done. * Energy is stored by forming energy-rich compounds * The amount of energy storage varies, but in fasting individuals it is zero or negative * Therefore, in an adult individual who has not eaten recently and who is not moving (or growing, reproducing, or lactating), all of the energy output appears as heat

Answer 1057

The standard unit of heat energy is the calorie, defined as the amount of heat energy necessary to raise the temperature of 1g of water 1°, from 15 to 16°C.

Answer 1058

* The **respiratory quotient (RQ)** is the ratio in the steady state of the volume of CO₂ produced by the volume of O₂ consumed per unit time * The **respiratory exchange ratio (R)** is the ratio of CO₂ to O₂ at any given time whether or not equilibrium has been reached * R is affected by factors other than embolism. * The RQ of carbohydrate is 1.00, and that of fat is about 0.70. This is because H and O are present in carbohydrate in the same proportions as in water, whereas in various fats, extra O₂ is necessary for the formation of H₂O. The RQ of protein has an average of 0.82

Answer 1059

* During hyperventilation, R rises because CO₂ is being blown off * During strenuous exercise, R may reach 2.00 because CO₂ is being blown off and lactic acid from anaerobic glycolysis is being converted to CO₂ * After exercise, R may fall for a while to 0.50 or less * In metabolic acidosis, R rises because respiratory compensation for the acidosis causes the amount of CO₂ expired to rise * In severe acidosis, R may be greater than 1.00 * In metabolic alkalosis, F falls

Answer 1060

* Muscular exertion during or just before measurement * Recent ingestion of food * High or low environmental temperature * Height, weight, and surface area * Sex * Age * Growth * Reproduction * Lactation * Emotional state * Body temperature * Circulating levels of thyroid hormones * Circulating epinephrine and norepinephrine levels

Answer 1061

* The SDA of a food is the obligatory energy expenditure that occurs during its assimilation into the body * It takes 30kcal to assimilate the amount of protein sufficiency to raise the metabolic rate 100kcl; 6kcal to assimilate a similar amount of carbohydrate and 5 kcal to assimilate a similar amount of fat.

Answer 1062

* The curve relating the metabolic rate to the environmental temperature is U-shaped. * When the environmental temperature is lower than body temperature, heat-producing mechanisms such as shivering are activated and the metabolic rate rises. * When the temperature is high enough to raise the body temperature, metabolic processes generally accelerate, and the metabolic rate rises about 14% for each degree Celsius of elevation

Answer 1063

* The metabolic rate determined at rest in a room at a comfortable temperature in the thermoneutral zone 12-14hours after the last meal is called the **basal metabolic rate**. The falls about 10% during sleep and up to 40% during prolonged starvation * The rate during normal daytime activities is higher than the BMR because of muscular activity and food intake. The **maximum metabolic rate** reached during exercise is often said to be 10 times the BMR, but trained athletes can increase their metabolic rate as much as 20-fold.

Answer 1064

About 2000kcal/day

Answer 1065

* Vitamin A and vitamin D are bound to transfer proteins in the circulation * The α-tocopherol form of vitamin E is normally bound to chylomicrons. In the liver, it is transferred to VLDLs and distributed to tissues by an α-tocopherol transfer protein

Answer 1066

* Peristalsis is a reflex response that is initiated when the gut wall is stretched by the contents of the lumen, and it occurs in all parts of the GI tract from the oesophagus to the rectum * The stretch initiates a circular contraction behind the stimulus and an area of relaxation in front of it * The wave of contraction then moves in an oral-to-caudal direction, propelling the contents of the lumen forward at rates that vary from 2-25cm/s.

Answer 1067

Peristaltic activity can be increased or decreased by the autonomic input to the gut, but its occurrence is independent of extrinsic innervation

Answer 1068

* It appears that local stretch releases serotonin, which activated sensory neurons that activate the myenteric plexus * Cholinergic neurons passing in a retrograde direction in this plexus activate neurons that release substance P and acetylcholine, causing smooth muscle contraction behind the bolus * At the same time, cholinergic neurons passing in an anterograde direction activate neurons that secrete NO and vasoactive intestinal polypeptide (VIP), producing the relaxation ahead of the stimulus.

Answer 1069

* Pharynx, oesophagus and stomach - 65cm * Duodenum - 25cm * Jejunum and ileum - 260cm * Colon 100cm

Answer 1070

* This motility pattern is known as segmentation, and it provides ample mixing of the intestinal contents (known as chyme) with the digestive juices * A segment of bowel contracts at both ends, and then a second contraction occurs in the centre of the segment to force the chyme both backward and forward. * Unlike peristalsis, therefore, retrograde movement of the chyme occurs routinely in the setting of segmentation. * This mixing pattern persists for as long as nutrients remain in the lumen to be absorbed.

Answer 1071

* The membrane potential fluctuates between about -65mV and -45mV * This **basis of electrical rhythm (BER)** is initiated by the **interstitial cells of Cajal**, stellate mesenchymal pacemaker cells with smooth muscle-like features that send long multiply branched processes into the intestinal smooth muscle. * In the stomach and the small intestine, these cells are located in the outer circular muscle layer near the myenteric plexus * In the colon, they are at the submucosal border of the circular muscle layer * In the stomach and small intestine, there is a descending gradient in pacemaker frequency, and as in the heart, the pacemaker with the highest frequency usually dominates

Answer 1072

* **Spike potentials** superimposed on the most depolarising portions of the BER waves to increase muscle tension * The depolarising portion of each spike is due to Ca^{2+^{influx and the repolarising portion is due to K^{+^{efflux.
* Acetylcholine increases the number of spikes and the tension of the smooth muscle
* Adrenaline decreases the number of spikes and the tension}}}}

Answer 1073

* 4/min in the stomach * 12/min in the duodenum * 8/min in the distal ileum * 2/min at the cecum * 6/min at the sigmoid

Answer 1074

* The function of the BER is to coordinate peristaltic and other motor activity, such as setting the rhythm of segmentation; contractions can occur only during the depolarising of the waves * After vagotomy or transection of the stomach wall, peristalsis in the stomach becomes irregular and chaotic

Answer 1075

* Cycles of motor activity migrate from the stomach to the distal ileum. * Each cycle, or migrating motor complex (MMC), starts with a quiescent period (phase I), continues with a period of irregular electrical and mechanical activity (phase II), and ends with a burst of regular activity (phase III) * The contractions migrate aborally at the rate of about 5cm/min, and also occur at intervals of approximately 100 minutes.

Answer 1076

* The MMCs are initiated by motilin. * The circulation level of this hormone increases at intervals of approximately 100 min in the interdigestive state, coordinated with the contractile pashes of the MMC * Gastric secretion, bile flow, and pancreatic secretion increase during each MMC. * They likely serve to clear the stomach and small intestine of luminal contents in preparation for the next meal

Answer 1077

* Secretion of motilin is suppressed and the MMC is abolished, until digestion and absorption are complete. * Instad, there is a return to peristalsis and the other forms of basic electrical rhythm and spike potentials during this time.

Answer 1078

* Chewing (mastication) breaks up large food particles and mixes the food with the secretions of the salivary glands. * This wetting and homogenising action aids swallowing and subsequent digestion. * Large food particles can be digested, but they cause strong and often painful contractions of the oesophageal musculature * Particles that are small tend to disperse in the absence of saliva and also make swallowing difficult because they do not form a bolus. * The number of chews that is optimal depends on the food, but usually ranges from 20 to 25.

Answer 1079

* Swallowing (deglutition) is a reflex response that is triggered by afferent impulses in the trigeminal, glossopharyngeal, and vagus nerves * These impulses are integrated in the nucleus of the tractus solitarious and the nucleus ambiguus * The efferent fibers pass to the pharyngeal musculature and the tongue via the trigeminal, facial and hypoglossal nerves.

Answer 1080

* Swallowing is initiated by the voluntary action of collecting the oral contents on the tongue and propelling them backward into the pharynx. * This starts a wave of involuntary contraction in the pharyngeal muscles that pushes the material into the oesophagus * Inhibition of respiration and glottic closure are part of the reflux response. * A peristalsis ring contraction of the oesophageal muscle forms behind the material, which is then swept down the oesophagus at a speed of approximately 4cm/s. * When humans are in an upright position, liquids, and semisolid foods generally fall by gravity to the lower oesophagus ahead of the peristaltic wave. However, if any food remains in the oesophagus, it is cleared by a second wave of peristalsis.

Answer 1081

* Unlike the rest of the oesophagus, the musculature of the gastroesophageal junction (**lower oesophageal sphincter**) is tonically active but relaxes on swallowing * The tonic activity of the sphincter between meals prevents reflux of gastric contents into the oesophagus.

Answer 1082

* The oesophageal smooth muscle is more prominent at the junction with the stomach (intrinsic sphincter). * Fibers of the crural portion at the diaphragm, a skeletal muscle, surround the oesophagus at this point (extrinsic sphincter) and exert a pinchcock-like action on the oesophagus. * In addition, the oblique or sling fibers of the stomach wall create a flap valve that helps close off the oesophagogastric junction and prevent regurgitation when intragastric pressure rises

Answer 1083

* Release of acetylcholine from vagal endings causes the intrinsic sphincter to contract, and the release of nitric oxide and VIP from interneurons innervated by other vagal fibers causes it to relax. * Contraction of the crural portion of the diaphragm, which is innervated but the phrenic nerves, is coordinated with respiration and contractions of chest and abdominal muscles. * Thus, the intrinsic and extrinsic sphincters operate together to permit orderly flow of food into the stomach and to prevent reflux of gastric contents into the oesophagus

Answer 1084

* Some air in unavoidably swallowed in the process of eating and drinking (**aerophagia**) * Some of the swallowed air is regurgitated (belching), and some of the gases it contains are absorbed, but much of it passes on to the colon * Here, some of the oxygen is absorbed, and hydrogen, hydrogen sulphide, carbon dioxide, and methane formed by the colonic bacteria from carbohydrates and other substrates are added to it * It is then expelled as **flatus**. The smell is largely due to sulphides.

Answer 1085

* The volume of gas normally found in the human GI tract is about 200mL, and the daily production is 500-1500mL

Answer 1086

* When food enters the stomach, the fundus and upper portion of the body relax and accommodate the food with little if any increase in pressure (**receptive relaxation**) * Peristalsis then begins in the, lower portion of the body, mixing and grinding the food and permitting small, semiliquid portions of it to pass through the pylorus and enter the duodenum

Answer 1087

* Receptive relaxation is, in part, vaguely mediated and triggered by movement of pharynx and oesophagus * Intrinsic reflexes also lead to relaxation as the stomach wall is stretched * Peristaltic waves controlled by the gastric BER begin soon thereafter and sweep toward the pylorus

Answer 1088

* The contraction of the distal stomach caused by each wave is sometimes called **antral systole** and can last up to 10 seconds. * Waves occur 3-4 times per minute.

Answer 1089

* Food rich in carbohydrate leaves the stomach in a few hours. Protein-rich food leaves more slowly, and emptying is slowest after a meal containing fat * The rate of emptying also depends on the osmotic pressure of the material entering the duodenum. Hyperosmolality of the duodenal contents is sensed by "duodenal osmoreceptors" that initiate a decrease in gastric emptying, which is probably neural in origin.

Answer 1090

* Vomiting starts with salivation and the sensation of nausea * Reverse peristalsis empties material from the upper part of the small intestine into the stomach * The glottis closes, preventing aspiration of vomitus into the trachea. The breath is held in mid inspiration * The muscles of the abdominal wall contract, and because the chest is held in a fixed position, the contraction increases intra-abdominal pressure. * The lower oesophageal sphincter and the oesophagus relax, and the gastric contents are ejected

Answer 1091

The "vomiting center" in the reticular formation of the medulla consists of scattered groups of neurons in this region that control the different components of the vomiting acts

Answer 1092

* Impulses are relayed from the mucosa to the medulla over visceral afferent pathways in the sympathetic nerves and vagi. * Other causes of vomiting can arise centrally. For example, afferents from the vestibular nuclei mediate the nausea and vomiting of motion sickness. * Other afferents presumably reach the vomiting control areas from the diencephalon and limbic system, because emetic responses to emotionally charged stimuli also occur

Answer 1093

* The **chemoreceptor trigger zone** in which these cells are located is in the **area postrema**, a V-shaped band of tissue on the lateral walls of the fourth ventricle near the obex * This structure is one of the circumventricular organs and is not protected by the blood brain barrier. * Lesions of the area postrema have little effect on the vomiting response to GI irritation or motion sickness, but abolish the vomiting that follows injection of morphine and a number of other emetic drugs.

Answer 1094

* Serotonin released from enterochromaffin cells in teh small intestine appears to vitiate impulses via 5-HT₃ receptors that trigger vomiting. * In addition, there are dopamine D₂ receptors and 5-HT₃ receptors in the area postrema and adjacent nucleus of the solitary tract * 5-HT₃ antagonists such as ondansetron and D₂ antagonists such as chlorpromazine and haloperidol are effect antiemetic agents

Answer 1095

* **Peristalsis** propels the intestinal contents (chyme) towards the large intestines * **Segmentation contractions**, move the chyme to and fro and increase its exposure to the mucosal surfaces. There contracts are initiated by focal increases in Ca²⁺ influx with waves of Ca²⁺ concentration spreading from each focus. * **Tonic contractions** are relatively prolonged contractions that in effect isolate one segment of the intestine from another.

Answer 1096

* Motility in this segment is slowed to allow the colon to absorb water, Na⁺, and other minerals * By removing about 90% of the fluid, it converts the 1000-2000mL of isotonic chyme that enters it each day from the ileum to about 200-250mL of semisolid faeces.

Answer 1097

* The ileum is linked to the colon by the ileocecal valve, which restricts reflux of colonic contents, and particularly the large numbers of commensal bacteria, into the relatively sterile ileum. * The portion of the ileum containing the valve projects slight into the cecum, so that increases in colonic pressure squeeze it shut, whereas increases in ileal pressure open it.

Answer 1098

* It is normally closed * Each time a peristaltic wave reaches it, it opens briefly, permitting some of the ileal chyme to squirt into the cecum * When food leaves the stomach, the cecum relaxes and the passage of chyme through the ileocecal valves increases (**gastroileal reflex**).

Answer 1099

* The **mass action contraction**, occurring about 10 times per day, in which there is simultaneous contraction of the smooth muscle over large confluent areas. * These contractions move material from one portion of the colon to another. They also move material into the rectum, and rectal distension initiates the defecation reflex.

Answer 1100

* The first part of a test meal reaches the cecum in about 4 hours in most individuals, and all the undigested portions have entered the colon in 8 or 9 hours. * On average, the first remnants of the meal traverse the first third of the colon in 6 hours, the second third in 9 hours, and reach the terminal part of the colon (the sigmoid colon) in 12 hours. * From the sigmoid colon to the anus, transport is much slower.

Answer 1101

* In humans, the sympathetic nerve supply to the internal (involuntary) the sphincter is excitatory, whereas the parasympathetic supply is inhibitory. This sphincter relaxes when the rectum is distended. * The nerve supply to the external anal sphnicter, a skeletal muscle, comes from the pudendal nerve. The sphincter is maintained in a state of tonic contraction, and moderate distension of the rectum increases the force of its contraction.

Answer 1102

* The urge to defecate first occurs when rectal pressure increases to about 18 mmHg * When this pressure reached 55mmHg, the external as well as the internal sphincter relaxes and there is reflex expulsion of the contents of the rectum * This is why reflux evacuation of the rectum can occur even in the setting of spinal injury

Answer 1103

* Normally, the angle between the anus and the rectum is approximately 90°, and this plus contraction of the puborectalis muscle inhibits defecation. * With straining, the abdominal muscles contract, the pelvic floor is lowered 1-3cm, and the puborectalis muscle relaxes. The anorectal angle is reduced to 15° or less. * This is combined with relaxation of the external anal sphincter and defecation occurs * Defecation is therefore a spinal reflex that can be voluntarily inhibited by keeping the external sphincter contracted or facilitated by relaxing the sphincter and contracting the abdominal muscles

Answer 1104

* Distension of the stomach by food initiates contractions of the rectum and, frequently, a desire to defecate * The response is called the **gastrocolic reflex**, and may be amplified by an action of gastrin on the colon. * Because of the response defecation after meals is the rule in children. * In adults, habit and cultural factors play a large role in determining when defecation occurs

Answer 1105

* Blood from the intestines and other viscera reach the liver via the portal vein. This blood percolates in sinusoids between plates of hepatic cells and eventually drains into the hepatic veins, which enter the inferior vena cava * During its passage through the hepatic plates, it is extensively modified chemically. Bile is formed on the other side at each plate. The bile passes to the intestine via the hepatic duct

Answer 1106

* In each hepatic lobule, the plates of hepatic cells are usually only one cell thick. * Large gaps occur between the endothelial cells, and the plasma is in intimate contact with the cells. * Hepatic artery blood also enters the sinusoids.

Answer 1107

The average transit time for blood across the liver lobule from the portal venal to the central hepatic vein is about 8.4 seconds.

Answer 1108

Numerous macrophages (**Kupffer cells**) are anchored to the endothelium of the sinusoids and project into the lumen

Answer 1109

* The canaliculi drain into intralobular bile ducts, and these coalesce via interlobular bile ducts to form the right and left hepatic ducts. * These ducts join outside the liver to form the common hepatic duct. * The cystic duct drains the gallbladder. * The hepatic duct unites with the cystic duct to form the common bile duct.

Answer 1110

* The common bile duct enters the duodenum at the duodenal papilla. * Its orifice is surrounded by the **sphincter of Oddi**, and it usually unites with the main pancreatic duct just before entering the duodenum * The sphincter is usually closed, but when the gastric contents enter the duodenum, cholecystokinin (CCK) is released and the GI hormone relaxes the sphincter and makes the gallbladder contract.

Answer 1111

* The walls of the extrahepatic ducts and the gallbladder contain fibrous tissue and smooth muscle. They are lined by a layer of columnar cells with scattered mucous glands. * In the gallbladder, the surface is extensively folded; this increases its surface area and gives the interior of the gallbladder a honeycombed appearance * The cystic duct is also folded to form the so-called spiral valves. This arrangement is believed to increase the turbulence of bile as it flows out of the gallbladder, thereby reducing the risk that it will precipitate and form gallstones.

Answer 1112

* Each acinus is at the end of the vascular stalk, containing terminal branches of portal veins, hepatic arteries, and bile ducts. * Blood flows from the centre of this functional unit to the terminal branches of the hepatic veins at the periphery. * The central portion of the acinus, zone 1, is well oxygenated. The intermediate zone (zone 2) is moderately well oxygenated. The peripheral zone (zone 3) is least well oxygenated and most susceptible to anoxic injury. * The hepatic veins drain into the inferior vena cava.

Answer 1113

* Portal venous pressure is normally about 10mmHg * Hepatic venous pressure is approximately 5mmHg. * The mean pressure in the hepatic artery branches that converge on the sinusoids is about 90mmHg * The pressure in the sinusoids is lower than the portal venous pressure, so a marked pressure drop occurs along the hepatic arterioles.

Answer 1114

* This pressure drop is adjusted so that there is an inverse relationship between hepatic arterial and portal venous blood flow. * This inverse relationship may be maintained in part by the rate at which adenosine is removed from the region around the arterioles. * Adenosine is produced by metabolism at a constant rate. When portal flow is reduced, it is wash away more slowly, and the local accumulation of adenosine dilates the terminal arterioles.

Answer 1115

* When portal flow to the liver from the intestine increases considerably, these "reserve" sinusoids are recruited. * This arrangement means that portal pressures do not increase linearly with portal flow until all sinusoids have been recruited. * This may be important to prevent fluid loss from the highly permeable liver under normal conditions. * If hepatic pressure are increased in disease states (cirrhosis), many litres of fluid can accumulate in the peritoneal cavity as **ascites**

Answer 1116

* It is innervated by noradrenergic vasoconstrictor nerve fibers reaching the liver via the 3rd to 11th thoracic ventral roots and the splanchnic nerves * The vasoconstrictor innervation of the hepatic artery comes from the hepatic sympathetic plexus * No known vasodilator fibers reach the liver

Answer 1117

* When systemic venous pressure rises, the portal vein radicles are dilated passively and the amount of blood in the liver increases. * In heart failure, the hepatic venous congestion may be extreme * Conversely, when diffuse noradrenergic discharge occurs in response to a drop in systemic blood pressure, the intrahepatic portal radicles constrict, portal pressure rises, and blood flow through the liver is brisk, bypassing most of the organ. * Most of the blood in the liver enters the systemic circulation. Constriction of the hepatic arterioles diverts blood from the liver, and constriction of the mesenteric arterioles reduced portal inflow. In severe shock, hepatic blood flow may be reduced to such a degree that patchy necrosis of the liver takes place.

Answer 1118

**Formation and secretion of bile** **Nutrient and vitamin metabolism** Glucose and other sugars Amino acids Lipids (fatty acids, cholesterol, lipoproteins) Fat-soluble vitamins Water-soluble vitamins **Inactivation of various substances** Toxins, steroids, other hormones **Synthesis of plasma proteins** Acute-phase proteins Albumin Clotting factors Steroid-binding and other hormone-binding proteins **Immunity** Kupffer cells

Answer 1119

* The bilirubin is bound to albumin in the circulation. Most of it is tightly bound, but some of it can dissociate in the liver, and free bilirubin enters liver cells via a member of the organic anion transporting polypeptide (OATP) family, and then becomes bound to cytoplasmic proteins * It is next conjugated to glucuronic acid in a reaction catalysed by the enzyme **glucuronyl transferase**. This enzyme is located primarily in the smooth endoplasmic reticulum. * Each bilirubin molecule reacts with two uridine diphosphoglucuronic acid molecules to form bilirubin diglucuronide. * This glucuronide, which is more water-soluble than the free bilirubin, is then transported against a concentration gradient most likely by an active transporter known as multi drug resistance protein-2 (MRP-2) into the bile canaliculi. * A small amount of the bilirubin glucuronide escapes into the blood, where it is found less tightly to albumin that is free bilirubin, and is excreted in the urine. * Thus, the total plasma bilirubin normally includes free bilirubin plus a small amount of conjugated bilirubin. Most of the bilirubin glucuronide passes via the bile ducts to the intestine.

Answer 1120

* Some of the bile pigments and urobilinogens are reabsorbed in the portal circulation. * Some of the reabsorbed substances are again excreted by the liver (via the enterohepatic circulation), but small amounts of urobilinogens enter the general circulation and are excreted in the urine

Answer 1121

1) Excess production of bilirubin (haemolytic anaemia) 2) Decreased uptake of bilirubin into hepatic cells 3) Disturbed intracellular protein binding or conjugation 4) Disturbed secretion of conjugated bilirubin into the bile canaliculi 5) Intrahepatic or extrahepatic bile duct obstruction When it is due to 1) - 3), the free bilirubin rises. When it is due to 4) and 5), bilirubin glucuronide regurgitates into the blood, and it is predominantly the conjugated bilirubin in the plasma that is elevated.

Answer 1122

* The list includes steroids and various drugs * These other compounds can compete with bilirubin for the enzyme system when they are present in appreciable amounts. * In addition, several barbiturates, antihistamines, anticonvulsants, and other compounds caused marked proliferation of the smooth endoplasmic reticulum in the hepatic cells, with a concurrent increase in hepatic glucuronyl transferase activity * Phenobarbital has been used successfully for the treatment of a congenital disease in which there is a relative deficiency of glucuronyl transferase

Answer 1123

* Ammonia levels must be carefully controlled because it is toxic to the CNS, and freely permeable across the blood-brain barrier. * The liver is the only organ in which the complete urea cycle (also known as the Krebs-Henseleit cycle) is expressed. * This converts circulating ammonia to urea, which can then be excreted in the urine

Answer 1124

* Ammonia in the circulation comes primarily from the colon and kidneys with lesser amounts deriving from the breakdown of red blood cells and from metabolism in the muscles. * As it passes through the liver, almost all of the ammonia in the circulation is cleared into the hepatocytes. * There, it is converted in the mitochondria to carbamoyl phosphate, which in turn reacts with ornithine to generate citrulline * A series of subsequent cytoplasm reactions eventually produce arginine, and this can be hydrated to urea and ornithine. * The latter returns to the mitochondria to begin another cycle, and urea, as a small molecule, diffuses readily back out into the sinusoidal blood. * It is then filtered in the kidneys and lost from the body in the urine

Answer 1125

* Bile acids, phosphatidylcholine, conjugated bilirubin, cholesterol, and xenobiotics. * Each of these enters the bile by means of a specific canalicular transporter. * It is the active secretion of bile acids, however, that is believed to be the primary driving force for the initial formation of canalicular bile. * Because they are osmotically active, the canalicular bile is transiently hypertonic * However the tight junctions that join adjacent hepatocytes are relatively permeable and thus a number of additional substances passively enter the bile from the plasma by diffusion. These substances include water, glucose, calcium, glutathione, amino acids, and urea.

Answer 1126

* The ratio of bile acids:phosphatidylcholine:cholesterol in canalicular bile is approximately 10:3:1. * Deviations from this ratio may cause cholesterol to precipitate, leading to one type of gallstones

Answer 1127

* The bile ductules are lined by cholangiocytes, specialised columnar epithelial cells. * Their tight junctions are less permeable than those of the hepatocytes, although they remain freely permeable to water and thus bile remains isotonic * The ductules scavenge plasma constituents, such as glucose and amino acids, and return them to the circulation by active transport. * Glutathione is also hydrolysed to its constituent amino acids by an enzyme, GGT, expressed on the apical membrane of the cholangiocytes * Removal of glucose and amino acids is likely important to prevent bacterial overgrowth, particularly during gallbladder storage. * The ductules also secrete bicarbonate in response to secretin in the postprandial period, as well as IgA and mucus for protection.

Answer 1128

**Hepatic bile duct** - 2-4% solids; 10-20mmol/L bile acids; pH 7.8-8.6 **Gallbladder bile** - 10-12% solids; 5-200mmol/L bile acids; 7.0-7.4pH

Answer 1129

* In the gallbladder, the bile is concentrated by absorption of water. * The degree of this concentration is shown by the increase in concentration of solids; hepatic bile is 97% water, whereas the average water content of gallbladder bike is 89% water.

Answer 1130

* Because the bile acids are a micellar solution, when the bile is concentrations, the micelles simply become larger, and since osmolarity is a colligative property, bile remains isotonic * However, bile become less alkaline as sodium ions are exchanged for protons (although the overall concentration of sodium ions rises with a concomitant loss of chloride and bicarbonate as the bile is concentrated).

Answer 1131

* Fatty acids and amino acids in the duodenum release CCK, which causes gallbladder contraction * The production of bile increased by stimulation of the vagus nerves and by the hormone secretin, which increases the water and bicarb content of bile. * Substances that increase the secretion of bile as known as **choleretics**. Bile acids themselves are among the most important physiologic choleretics

Answer 1132

* The two lobes of the human thyroid are connected by a bridge of tissue, the thyroid isthmus, and there is sometimes a pyramidal lobe arising from the isthmus in front of the larynx. * The gland is well vascularized, and the thyroid has one of the highest rates of blood flow per gram of tissue of any organ in the body.

Answer 1133

* The portion of the thyroid concerned with the production of thyroid hormone consists of multiple acini (follicles). * Each spherical follicle is surrounded by a single layer of polarized epithelial cells and filled with pink-staining proteinaceous material called colloid. Colloid consists predominantly of the glycoprotein, thyroglobulin. * When the gland is inactive, the colloid is abundant, the follicles are large, and the cells lining them are flat. * When the gland is active, the follicles are small, the cells are cuboid or columnar, and areas where the colloid is being actively reabsorbed into the thyrocytes are visible as “reabsorption lacunae”

Answer 1134

* Microvilli project into the colloid from the apexes of the thyroid cells and canaliculi extend into them. * The endoplasmic reticulum is prominent, a feature common to most glandular cells, and secretory granules containing thyroglobulin are seen. * The individual thyroid cells rest on a basal lamina that separates them from the adjacent capillaries. * The capillaries are fenestrated, like those of other endocrine glands

Answer 1135

* The primary hormone secreted by the thyroid is thyroxine (T4), along with much lesser amounts of triiodothyronine (T3). * T3 has much greater biologic activity than T4 and is specifically generated at its site of action in peripheral tissues by deiodination of T4

Answer 1136

* The minimum daily iodine intake that will maintain normal thyroid function is 150 μg in adults. * The principal organs that take up circulating I^- are the thyroid, which uses it to make thyroid hormones, and the kidneys, which excrete it in the urine. * About 120 μg/day enter the thyroid at normal rates of thyroid hormone synthesis and secretion. * The thyroid secretes 80 μg/day in the form of T3 and T4, while 40 μg/day diffuses back into the extracellular fluid (ECF). * Circulating T3 and T4 are metabolized in the liver and other tissues, with the release of a further 60 μg of I^– per day into the ECF. * Some thyroid hormone derivatives are excreted in the bile, and some of the iodine in them is reabsorbed (enterohepatic circulation), but there is a net loss of I^– in the stool of approximately 20 μg/day. * The total amount of I^– entering the ECF is thus 500 + 40 + 60, or 600 μg/day; 20% of this I^{–^{enters the thyroid, whereas 80% is excreted in the urine.}}

Answer 1137

* The basolateral membranes of thyrocytes facing the capillaries contain a symporter that transports two Na⁺ ions and one I^– ion into the cell with each cycle, against the electrochemical gradient for I^–. * This Na⁺/^I– symporter (NIS) is capable of producing intracellular I^– concentrations that are 20–40 times as great as the concentration in plasma. * The process involved is secondary active transport, with the energy provided by active transport of Na+ out of thyroid cells by Na, K ATPase. * NIS is regulated both by transcriptional means and by active trafficking into and out of the thyrocyte basolateral membrane; in particular, thyroid-stimulating hormone (TSH) induces both NIS expression and the retention of NIS in the basolateral membrane, where it can mediate sustained iodide uptake.

Answer 1138

* Iodide must also exit the thyrocyte across the apical membrane to access the colloid, where the initial steps of thyroid hormone synthesis occur. * This transport step is believed to be mediated, at least in part, by a Cl–/I– exchanger known as pendrin. * This protein was first identified as the product of the gene responsible for the Pendred syndrome, which causes thyroid dysfunction and deafness. * Pendrin (SLC26A4) is one member of the larger family of SLC26 anion exchangers.

Answer 1139

* At the interface between the thyrocyte and the colloid, iodide undergoes a process referred to as organification. * First, it is oxidized to iodine, and then incorporated into the carbon 3 position of tyrosine residues that are part of the thyroglobulin molecule in the colloid. * Thyroglobulin is synthesized in the thyroid cells and secreted into the colloid by exocytosis of granules. * The oxidation and reaction of iodide with the secreted thyroglobulin is mediated by thyroid peroxidase, a membrane-bound enzyme found in the thyrocyte apical membrane. * The thyroid hormones so produced remain part of the thyroglobulin molecule until needed.

Answer 1140

* When there is a need for thyroid hormone secretion, colloid is internalized by the thyrocytes by endocytosis, and directed toward lysosomal degradation. * Thus, the peptide bonds of thyroglobulin are hydrolyzed, and free T4 and T3 are discharged into cytosol and thence to the capillaries.

Answer 1141

* They collect and transport iodine * They synthesize thyroglobulin and secrete it into the colloid * They fix iodine to the thyroglobulin to generate thyroid hormones * They remove the thyroid hormones from thyroglobulin and secrete them into the circulation.

Answer 1142

* Most of the T3 and RT3 are formed from T4 deiodination in the tissues and only small amounts are secreted by the thyroid. * T4 is also conjugated for subsequent excretion from the body.

Answer 1143

* T4 and T3 are relatively lipophilic; thus, their free forms in plasma are in equilibrium with a much larger pool of protein-bound thyroid hormones in plasma and in tissues. * Free thyroid hormones are added to the circulating pool by the thyroid. * It is the free thyroid hormones in plasma that are physiologically active and that feed back to inhibit pituitary secretion of TSH. * The function of protein-binding appears to be the maintenance of a large pool of hormone that can readily be mobilized as needed. * In addition, at least for T3, hormone binding prevents excess uptake by the first cells encountered and promotes uniform tissue distribution.

Answer 1144

* The plasma proteins that bind thyroid hormones are **albumin**, a prealbumin called **transthyretin** (formerly called thyroxine-binding prealbumin), and a globulin known as **thyroxine-binding globulin** (TBG). * Of the three proteins, albumin has the largest capacity to bind T4 (ie, it can bind the most T4 before becoming saturated) and TBG has the smallest capacity. * However, the affinities of the proteins for T4 (ie, the avidity with which they bind T4 under physiologic conditions) are such that most of the circulating T4 is bound to TBG, with over a third of the binding sites on the protein occupied. * Smaller amounts of T4 are bound to transthyretin and albumin. * The half-life of transthyretin is 2 days, that of TBG is 5 days, and that of albumin is 13 days.

Answer 1145

* Normally, 99.98% of the T4 in plasma is bound; the free T4 level is only about 2 ng/dL. There is very little T4 in the urine. * Its biologic half-life is long (about 6–7 days), and its volume of distribution is less than that of ECF (10 L, or about 15% of body weight). * All of these properties are characteristic of a substance that is strongly bound to protein.

Answer 1146

* T3 is not bound to quite as great an extent; of the 0.15 μg/dL normally found in plasma, 0.2% (0.3 ng/dL) is free. * The remaining 99.8% is protein-bound, 46% to TBG and most of the remainder to albumin, with very little binding to transthyretin. * The lesser binding of T3 correlates with the facts that T3 has a shorter half-life than T4 and that its action on the tissues is much more rapid. * RT3 also binds to TBG.

Answer 1147

* T4 and T3 are deiodinated in the liver, the kidneys, and many other tissues. * These deiodination reactions serve not only to catabolize the hormones, but also to provide a local supply specifically of T3, which is believed to be the primary mediator of the physiologic effects of thyroid secretion. * One third of the circulating T4 is normally converted to T3 in adult humans, and 45% is converted to RT3. * Only about 13% of the circulating T3 is secreted by the thyroid while 87% is formed by deiodination of T4; similarly, only 5% of the circulating RT3 is secreted by the thyroid and 95% is formed by deiodination of T4. * It should be noted as well that marked differences in the ratio of T3 to T4 occur in various tissues. Two tissues that have very high T3/T4 ratios are the pituitary and the cerebral cortex, due to the expression of specific deiodinases

Answer 1148

* D1, D2, and D3. * All are unique in that they contain the rare amino acid selenocysteine, with selenium in place of sulfur, which is essential for their enzymatic activity. * D1 is present in high concentrations in the liver, kidneys, thyroid, and pituitary. It appears primarily to be responsible for maintaining the formation of T3 from T4 in the periphery. * D2 is present in the brain, pituitary, and brown fat. It also contributes to the formation of T3. * D3 is also present in the brain and in reproductive tissues. * Overall, the deiodinases appear to be responsible for maintaining differences in T3/T4 ratios in the various tissues in the body.

Answer 1149

* TSH secretion is increased by the hypothalamic hormone TRH and inhibited in a negative feedback manner by circulating free T4 and T3. * The effect of T4 is enhanced by production of T3 in the cytoplasm of the pituitary cells by the 5′-D2 they contain. * TSH secretion is also inhibited by stress, and in experimental animals it is increased by cold and decreased by warmth.

Answer 1150

* Within a few minutes after the injection of TSH, there are increases in iodide binding, synthesis of T3, T4, and iodotyrosines, secretion of thyroglobulin into the colloid, and endocytosis of colloid. * Iodide trapping is increased in a few hours; blood flow increases; * With long-term TSH treatment, the cells hypertrophy and the weight of the gland increases.

Answer 1151

* Some of the widespread effects of thyroid hormones in the body are secondary to stimulation of O2 consumption (calorigenic action) * Affect growth and development in mammals * Help regulate lipid metabolism, and increase the absorption of carbohydrates from the intestine * They also increase the dissociation of oxygen from hemoglobin by increasing red cell 2,3-diphosphoglycerate (DPG)

Answer 1152

* Thyroid hormones enter cells and T3 binds to TR in the nuclei. T4 can also bind, but not as avidly. * The hormone–receptor complex then binds to DNA via zinc fingers and increases (or in some cases, decreases) the expression of a variety of different genes that code for proteins that regulate cell function. * Thus, the nuclear receptors for thyroid hormones are members of the superfamily of hormone-sensitive nuclear transcription factors.

Answer 1153

In most of its actions, T3 acts more rapidly and is three to five times more potent than T4. This is because T3 is less tightly bound to plasma proteins than is T4, but binds more avidly to thyroid hormone receptors.

Answer 1154

* T4 and T3 increase the O2 consumption of almost all metabolically active tissues. * The exceptions are the adult brain, testes, uterus, lymph nodes, spleen, and anterior pituitary. * T4 actually depresses the O2 consumption of the anterior pituitary, presumably because it inhibits TSH secretion. * The increase in metabolic rate produced by a single dose of T4 becomes measurable after a latent period of several hours and lasts 6 days or more.

Answer 1155

* An epinephrine-secreting type that has larger, less dense granules * A norepinephrine-secreting type in which smaller, very dense granules fail to fill the vesicles in which they are contained. * In humans, 90% of the cells are the epinephrine-secreting type and 10% are the norepinephrine-secreting type.

Answer 1156

* Norepinephrine is formed by hydroxylation and decarboxylation of tyrosine * Epinephrine is formed by methylation of norepinephrine. * Phenylethanolamine-N-methyltransferase (PNMT), the enzyme that catalyzes the formation of epinephrine from norepinephrine, is found in appreciable quantities only in the brain and the adrenal medulla. * Adrenal medullary PNMT is induced by glucocorticoids. Although relatively large amounts are required, the glucocorticoid concentration is high in the blood draining from the cortex to the medulla.

Answer 1157

* For the most part, they are methoxylated and then oxidized to 3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid [VMA]). * About 50% of the secreted catecholamines appear in the urine as free or conjugated metanephrine and normetanephrine, and 35% as VMA. * Only small amounts of free norepinephrine and epinephrine are excreted. * In normal humans, about 30 μg of norepinephrine, 6 μg of epinephrine, and 700 μg of VMA are excreted per day.

Answer 1158

In addition to mimicking the effects of noradrenergic nervous discharge, norepinephrine and epinephrine exert metabolic effects that include glycogenolysis in liver and skeletal muscle, mobilization of free fatty acids (FFA), increased plasma lactate, and stimulation of the metabolic rate.

Answer 1159

* ACTH binds to high-affinity receptors on the plasma membrane of adrenocortical cells. * This activates adenylyl cyclase via Gs. * The resulting reactions lead to a prompt increase in the formation of pregnenolone and its derivatives, with secretion of the latter. * Over longer periods, ACTH also increases the synthesis of the P450s involved in the synthesis of glucocorticoids.

Answer 1160

* **Parathyroid hormone (PTH)** is secreted by the parathyroid glands. Its main action is to mobilize calcium from bone and increase urinary phosphate excretion. * **1,25-Dihydroxycholecalciferol** is a steroid hormone formed from vitamin D by successive hydroxylations in the liver and kidneys. Its primary action is to increase calcium absorption from the intestine. * **Calcitonin**, a calcium-lowering hormone that in mammals is secreted primarily by cells in the thyroid gland, inhibits bone resorption.

Answer 1161

* It is the free, ionized calcium (Ca2+) in the body fluids that is a vital second messenger and is necessary for blood coagulation, muscle contraction, and nerve function. * A decrease in extracellular Ca2+ exerts a net excitatory effect on nerve and muscle cells in vivo. * The result is hypocalcemic tetany, which is characterized by extensive spasms of skeletal muscle, involving especially the muscles of the extremities and the larynx. * Laryngospasm can become so severe that the airway is obstructed and fatal asphyxia is produced. * Ca2+ also plays an important role in blood clotting, but in vivo, fatal tetany would occur before compromising the clotting reaction.

Answer 1162

* Symptoms of tetany appear at higher total calcium levels if the patient hyperventilates, thereby increasing plasma pH. * Plasma proteins are more ionized when the pH is high, providing more protein anions to bind with Ca²⁺

Answer 1163

* A readily exchangeable reservoir and a much larger pool of stable calcium that is only slowly exchangeable. * Two independent but interacting homeostatic systems affect the calcium in bone. * One is the system that regulates plasma Ca^{2+^{, providing for the movement of about 500 mmol of Ca²⁺ per day into and out of the readily exchangeable pool in the bone.
* The other system involves bone remodeling by the constant interplay of bone resorption and deposition.
* However, the Ca^{2+^{interchange between plasma and this stable pool of bone calcium is only about 7.5 mmol/d.}}}}

Answer 1164

* Ca²⁺ is transported across the brush border of intestinal epithelial cells via channels known as transient receptor potential vanilloid type 6 (TRPV6) and binds to an intracellular protein known as calbindin-D9k. * Calbindin-D9k sequesters the absorbed calcium so that it does not disturb epithelial signaling processes that involve calcium. * The absorbed Ca²⁺ is thereby delivered to the basolateral membrane of the epithelial cell, from where it can be transported into the bloodstream by either a Na⁺/Ca²⁺ exchanger (NCX1) or a Ca²⁺-dependent ATPase. * The overall transport process is regulated by 1,25-dihydroxycholecalciferol. As Ca2+ uptake rises, moreover, 1,25-dihydroxycholecalciferol levels fall in response to increased plasma Ca2+

Answer 1165

* Plasma Ca²⁺ is filtered in the kidneys, but 98–99% of the filtered Ca^{2+^{is reabsorbed.
* About 60% of the reabsorption occurs in the proximal tubules and the remainder in the ascending limb of the loop of Henle and the distal tubule.
* Distal tubular reabsorption depends on the TRPV5 channel, which is related to TRPV6 discussed previously, and whose expression is regulated by PTH.}}

Answer 1166

* P_I in the plasma is filtered in the glomeruli, and 85–90% of the filtered P_I is reabsorbed. * Active transport in the proximal tubule accounts for most of the reabsorption and involves two related sodium-dependent P_I cotransporters, NaPi-IIa and NaPi-IIc. * NaPi-IIa is powerfully inhibited by PTH, which causes its internalization and degradation and thus a reduction in renal Pi reabsorption

Answer 1167

* Vitamin D3, which is also called cholecalciferol, is produced in the skin of mammals from 7-dehydrocholesterol by the action of sunlight. * The reaction involves the rapid formation of previtamin D3, which is then converted more slowly to vitamin D3. * Vitamin D3 and its hydroxylated derivatives are transported in the plasma bound to a globulin, vitamin D-binding protein (DBP). * Vitamin D3 is also ingested in the diet.

Answer 1168

* Vitamin D3 is metabolized by enzymes that are members of the cytochrome P450 (CYP) superfamily. * In the liver, vitamin D3 is converted to 25-hydroxycholecalciferol (calcidiol, 25-OHD3). * The 25-hydroxycholecalciferol is converted in the cells of the proximal tubules of the kidneys to the more active metabolite 1,25-dihydroxycholecalciferol, which is also called calcitriol or 1,25-(OH)2D3. * 1,25-Dihydroxycholecalciferol is also made in the placenta, in keratinocytes in the skin, and in macrophages. * The normal plasma level of 25-hydroxycholecalciferol is about 30 ng/mL, and that of 1,25-dihydroxycholecalciferol is about 0.03 ng/mL (approximately 100 pmol/L). * The less active metabolite 24,25-dihydroxycholecalciferol is also formed in the kidneys.

Answer 1169

* 1,25-Dihydroxycholecalciferol stimulates the expression of a number of gene products involved in Ca2+ transport and handling via its receptor, which acts as a transcriptional regulator in its ligand-bound form. * One group is the family of calbindin-D proteins. These are members of the troponin C superfamily of Ca2+-binding proteins that also includes calmodulin. * 1,25-Dihydroxycholecalciferol also increases the number of Ca²⁺–ATPase and TRPV6 molecules in the intestinal cells, and thus, the overall capacity for absorption of dietary calcium. * 1,25-dihydroxycholecalciferol facilitates Ca2+ reabsorption in the kidneys via increased TRPV5 expression in the proximal tubules, increases the synthetic activity of osteoblasts, and is necessary for normal calcification of matrix. * The stimulation of osteoblasts brings about a secondary increase in the activity of osteoclasts

Answer 1170

* When the plasma Ca²⁺ level is high, little 1,25-dihydroxycholecalciferol is produced, and the kidneys produce the relatively inactive metabolite 24,25-dihydroxycholecalciferol instead. * This effect of Ca²⁺ on production of 1,25-dihydroxycholecalciferol is the mechanism that brings about adaptation of Ca²⁺ absorption from the intestine. * Conversely, expression of 1α-hydroxylase is stimulated by PTH, and when the plasma Ca²⁺ level is low, PTH secretion is increased. * The production of 1,25-dihydroxycholecalciferol is also increased by low plasma PO₄^3– levels and inhibited by high plasma PO₄ ^3– levels, by a direct inhibitory effect of PO₄^3– on the 1α-hydroxylase. * Additional control of 1,25-dihydroxycholecalciferol formation results from a direct negative feedback effect of the metabolite on 1α-hydroxylase, a positive feedback action on the formation of 24,25-dihydroxycholecalciferol, and a direct action on the parathyroid gland to inhibit PTH expression.

Answer 1171

* The abundant chief cells, which contain a prominent Golgi apparatus plus endoplasmic reticulum and secretory granules, synthesize and secrete PTH. * The less abundant and larger oxyphil cells contain oxyphil granules and large numbers of mitochondria in their cytoplasm.

Answer 1172

* The normal plasma level of intact PTH is 10–55 pg/mL. * The half-life of PTH is approximately 10 min, and the secreted polypeptide is rapidly cleaved by the Kupffer cells in the liver into fragments that are probably biologically inactive. * PTH and these fragments are then cleared by the kidneys.

Answer 1173

* PTH acts directly on bone to increase bone resorption and mobilize Ca²⁺. * In addition to increasing plasma Ca²⁺, PTH increases phosphate excretion in the urine and thereby depresses plasma phosphate levels. * This phosphaturic action is due to a decrease in reabsorption of phosphate via effects on NaPi-IIa in the proximal tubules. * PTH also increases reabsorption of Ca in the distal tubules, although Ca²⁺ excretion in the urine is often increased in hyperparathyroidism because the increase in the load of filtered calcium overwhelms the effect on reabsorption. * PTH also increases the formation of 1,25-dihydroxycholecalciferol, and this increases Ca²⁺ absorption from the intestine. * On a longer time scale, PTH stimulates both osteoblasts and osteoclasts.

Answer 1174

* The signs and symptoms of hypoparathyroidism develop but the circulating level of PTH is normal or even elevated. * Because tissues fail to respond to the hormone, this is a receptor disease. * There are two forms. In the more common form, a congenital 50% reduction of the activity of Gs occurs and PTH fails to produce a normal increase in cAMP concentration. In a different, less common form, the cAMP response is normal but the phosphaturic action of the hormone is defective.

Answer 1175

* Circulating Ca²⁺ acts directly on the parathyroid glands in a negative feedback manner to regulate the secretion of PTH. * The key to this regulation is a cell membrane Ca²⁺ sensing receptor, CaSR. Activation of this G-protein–coupled receptor in the parathyroid inhibits PTH secretion. * In this way, when the plasma Ca²⁺ level is high, PTH secretion is inhibited and Ca²⁺ is deposited in the bones. When it is low, secretion is increased and Ca²⁺ is mobilized from the bones. * 1,25-Dihydroxycholecalciferol acts directly on the parathyroid glands to decrease preproPTH mRNA. * Increased plasma phosphate stimulates PTH secretion by lowering plasma levels of free Ca²⁺ and inhibiting the formation of 1,25-dihydroxycholecalciferol.

Answer 1176

In mammals, calcitonin is produced by the parafollicular cells of the thyroid gland, which are also known as the clear or C cells.

Answer 1177

* Its secretion is increased when the thyroid gland is exposed to a plasma calcium level of approximately 9.5 mg/dL. * Above this level, plasma calcitonin is directly proportional to plasma calcium. * β-Adrenergic agonists, dopamine, and oestrogens also stimulate calcitonin secretion. Gastrin, cholecystokinin (CCK), glucagon, and secretin have also been reported to stimulate calcitonin secretion, with gastrin being the most potent stimulus

Answer 1178

* Receptors for calcitonin are found in bones and the kidneys. * Calcitonin lowers circulating calcium and phosphate levels. * It exerts its calcium-lowering effect by inhibiting bone resorption. This action is direct, and calcitonin inhibits the activity of osteoclasts in vitro. * It also increases Ca²⁺ excretion in the urine.

Answer 1179

* **Glucocorticoids** lower plasma Ca²⁺ levels by inhibiting osteoclast formation and activity, but over long periods they cause osteoporosis by decreasing bone formation and increasing bone resorption. They decrease bone formation by inhibiting protein synthesis in osteoblasts. They also decrease the absorption of Ca²⁺ and PO₄^3– from the intestine and increase the renal excretion of these ions. The decrease in plasma Ca²⁺ concentration also increases the secretion of PTH, and bone resorption is facilitated. * **Growth hormone** increases Ca2+ excretion in the urine, but it also increases intestinal absorption of Ca2+ and this effect may be greater than the effect on excretion, with a resultant positive calcium balance. * **Thyroid hormones** may cause hypercalcemia, hypercalciuria, and, in some instances, osteoporosis * **Oestrogens** prevent osteoporosis by inhibiting the stimulatory effects of certain cytokines on osteoclasts. * **Insulin** increases bone formation, and there is significant bone loss in untreated diabetes.

Answer 1180

* The naturally occurring estrogens are **17β-estradiol, estrone, and estriol**. * They are secreted primarily by the granulosa cells of the ovarian follicles, the corpus luteum, and the placenta.

Answer 1181

* Two of these, **insulin and glucagon**, are hormones and have important functions in the regulation of the intermediary metabolism of carbohydrates, proteins, and fats. * The third polypeptide, **somatostatin**, plays a role in the regulation of islet cell secretion * The fourth, **pancreatic polypeptide**, is probably concerned primarily with the regulation of ion transport in the intestine. * Glucagon, somatostatin, and possibly pancreatic polypeptide are also secreted by cells in the mucosa of the gastrointestinal tract.

Answer 1182

* Insulin is anabolic, increasing the storage of glucose, fatty acids, and amino acids. * Glucagon is catabolic, mobilizing glucose, fatty acids, and the amino acids from stores into the bloodstream. * The two hormones are thus reciprocal in their overall action and are reciprocally secreted in most circumstances. * Insulin excess causes hypoglycemia, which leads to convulsions and coma. Insulin deficiency, either absolute or relative, causes diabetes mellitus (chronic elevated blood glucose), a complex and debilitating disease that if untreated is eventually fatal. * Glucagon deficiency can cause hypoglycemia, and glucagon excess makes diabetes worse. * Excess pancreatic production of somatostatin causes hyperglycemia and other manifestations of diabetes.

Answer 1183

* The A cells secrete glucagon, the B cells secrete insulin, the D cells secrete somatostatin, and the F cells secrete pancreatic polypeptide. * The B cells, which are the most common and account for 60–75% of the cells in the islets, are generally located in the center of each islet. * They tend to be surrounded by the A cells, which make up 20% of the total, and the less common D and F cells. * The islets in the tail, the body, and the anterior and superior part of the head of the human pancreas have many A cells and few if any F cells in the outer rim, whereas the islets in the posterior part of the head of the pancreas have a relatively large number of F cells and few A cells.

Answer 1184

* Insulin is synthesized in the rough endoplasmic reticulum of the B cells. * It is then transported to the Golgi apparatus, where it is packaged into membrane-bound granules. * These granules move to the plasma membrane by a process involving microtubules, and their contents are expelled by exocytosis. * The insulin then crosses the basal lamina of the B cell and a neighboring capillary and the fenestrated endothelium of the capillary to reach the bloodstream.

Answer 1185

* Like other polypeptide hormones and related proteins that enter the endoplasmic reticulum, insulin is synthesized as part of a larger preprohormone * Preproinsulin originates from the endoplasmic reticulum. * The remainder of the molecule is then folded, and the disulfide bonds are formed to make proinsulin. * The peptide segment connecting the A and B chains, the connecting peptide (C peptide), facilitates the folding and then is detached in the granules before secretion. * Two proteases are involved in processing the proinsulin. * Normally, 90–97% of the product released from the B cells is insulin along with equimolar amounts of C peptide. The rest is mostly proinsulin. * C peptide can be measured by radioimmunoassay, and its level in blood provides an index of B cell function in patients receiving exogenous insulin.

Answer 1186

* Plasma contains a number of substances with insulin-like activity in addition to insulin. The activity that is not suppressed by anti-insulin antibodies has been called non-suppressible insulin-like activity (NSILA). * Most, if not all, of this activity persists after pancreatectomy and is due to the insulin-like growth factors IGF-I and IGF-II. * These IGFs are polypeptides. Small amounts are free in the plasma (low-molecular-weight fraction), but large amounts are bound to proteins (high-molecular-weight fraction).

Answer 1187

* The half-life of insulin in the circulation in humans is about 5 min. * Insulin binds to insulin receptors, and some is internalized. * It is destroyed by proteases in the endosomes formed by the endocytotic process.

Answer 1188

**Rapid** Increased transport of glucose, amino acids, and K+ into insulin-sensitive cells **Intermediate** Stimulation of protein synthesis Inhibition of protein degradation Activation of glycolytic enzymes and glycogen synthase Inhibition of phosphorylase and gluconeogenic enzymes **Delayed** Increase in mRNAs for lipogenic and other enzymes

Answer 1189

**Adipose tissue** Increased glucose entry, fatty acid synthesis, glycerol phosphate synthesis, triglyceride deposition, K⁺ uptake Activation of lipoprotein lipase Inhibition of hormone-sensitive lipase **Muscle** Increased glucose entry, glycogen synthesis, amino acid uptake, protein synthesis in ribosomes, ketone uptake, K⁺ uptake Decreased protein catabolism and release of gluconeogenic amino acids **Liver** Decreased ketogenesis, glucose output due to decreased gluconeogenesis Increased glycogen synthesis, and increased glycolysis, protein synthesis, lipid synthesis

Answer 1190

In muscle, adipose, and some other tissues, insulin stimulates glucose entry into cells by increasing the number of glucose transporters (GLUTs) in the cell membranes.

Answer 1191

* GLUT-4 is the transporter in muscle and adipose tissue that is stimulated by insulin. * A pool of GLUT-4 molecules is maintained within vesicles in the cytoplasm of insulin-sensitive cells. * When the insulin receptors of these cells are activated, the vesicles move rapidly to the cell membrane and fuse with it, inserting the transporters into the cell membrane. * When insulin action ceases, the transporter-containing patches of membrane are endocytosed and the vesicles are ready for the next exposure to insulin. * Activation of the insulin receptor brings about the movement of the vesicles to the cell membrane by activating phosphatidylinositol 3-kinase.

Answer 1192

* Growth hormone and cortisol both inhibit phosphorylation in certain tissues. * Transport is normally so rapid that it is not a rate-limiting step in glucose metabolism. * However, it is rate-limiting in B cells.

Answer 1193

Instead, it induces glucokinase, and this increases the phosphorylation of glucose, so that the intracellular free glucose concentration stays low, facilitating the entry of glucose into the cell.

Answer 1194

* Insulin-sensitive tissues also contain a population of GLUT-4 vesicles that move into the cell membrane in response to exercise, a process that occurs independent of the action of insulin. This is why exercise lowers blood sugar. * A 5’-adenosine monophosphate (AMP)–activated kinase may trigger the insertion of these vesicles into the cell membrane.

Answer 1195

* The maximal decline in plasma glucose occurs 30 min after intravenous injection of insulin. * After subcutaneous administration, the maximal fall occurs in 2–3 h.

Answer 1196

* Insulin causes K⁺ to enter cells, with a resultant lowering of the extracellular K⁺ concentration. * Infusions of insulin and glucose significantly lower the plasma K⁺ level in normal individuals and are very effective for the temporary relief of hyperkalemia in patients with renal failure. * Hypokalemia often develops when patients with diabetic acidosis are treated with insulin. * The reason for the intracellular migration of K⁺ is still uncertain. However, insulin increases the activity of Na, K ATPase in cell membranes, so that more K⁺ is pumped into cells.

Answer 1197

* The action on glycogen synthase fosters glycogen storage, and the actions on glycolytic enzymes favour glucose metabolism to two carbon fragments, with resulting promotion of lipogenesis. * Stimulation of protein synthesis from amino acids entering the cells and inhibition of protein degradation foster growth.

Answer 1198

* Binding of insulin triggers the tyrosine kinase activity of the β subunits, producing autophosphorylation of the β subunits on tyrosine residues. * The autophosphorylation, which is necessary for insulin to exert its biologic effects, triggers phosphorylation of some cytoplasmic proteins and dephosphorylation of others, mostly on serine and threonine residues. Insulin receptor substrate (IRS-1) mediates some of the effects in humans but there are other effector systems as well.

Answer 1199

* Fifty percent of an ingested glucose load is normally burned to CO2 and H2O; 5% is converted to glycogen; and 30–40% is converted to fat in the fat depots. * In diabetes, less than 5% of ingested glucose is converted to fat, despite a decrease in the amount burned to CO2 and H2O, and no change in the amount converted to glycogen. * Therefore, glucose accumulates in the bloodstream and spills over into the urine.

Answer 1200

* Glucose enters the B cells via GLUT-2 transporters and is phosphorylated by glucokinase then metabolized to pyruvate in the cytoplasm. * The pyruvate enters the mitochondria and is metabolized to CO2 and H2O via the citric acid cycle with the formation of ATP by oxidative phosphorylation. * The ATP enters the cytoplasm, where it inhibits ATP-sensitive K⁺ channels, reducing K⁺ efflux. * This depolarizes the B cell, and Ca²⁺ enters the cell via voltage-gated Ca²⁺ channels. * The Ca²⁺ influx causes exocytosis of a readily releasable pool of insulin-containing secretory granules, producing the initial spike of insulin secretion.

Answer 1201

* Metabolism of pyruvate via the citric acid cycle also causes an increase in intracellular glutamate. * The glutamate appears to act on a second pool of secretory granules, committing them to the releasable form. * The action of glutamate may be to decrease the pH in the secretory granules, a necessary step in their maturation. * The release of these granules then produces the prolonged second phase of the insulin response to glucose. * Thus, glutamate appears to act as an intracellular second messenger that primes secretory granules for secretion.

Answer 1202

* Insulin stimulates the incorporation of amino acids into proteins and combats the fat catabolism that produces the β-keto acids. * Therefore, it is not surprising that arginine, leucine, and certain other amino acids stimulate insulin secretion, as do β–keto acids such as acetoacetate. * Like glucose, these compounds generate ATP when metabolized, and this closes ATP-sensitive K+ channels in the B cells. * In addition, L-arginine is the precursor of NO, and NO stimulates insulin secretion.

Answer 1203

* Catecholamines have a dual effect on insulin secretion; they inhibit insulin secretion via α2-adrenergic receptors and stimulate insulin secretion via β-adrenergic receptors. * The net effect of epinephrine and norepinephrine is usually inhibition. * However, if catecholamines are infused after administration of α-adrenergic blocking drugs, the inhibition is converted to stimulation

Answer 1204

* Branches of the right vagus nerve innervate the pancreatic islets, and stimulation of this parasympathetic pathway causes increased insulin secretion via M4 receptors * Atropine blocks the response and acetylcholine stimulates insulin secretion. * The effect of acetylcholine, like that of glucose, is due to increased cytoplasmic Ca2+, but acetylcholine activates phospholipase C, with the released IP3 releasing the Ca2+ from the endoplasmic reticulum.

Answer 1205

* Stimulation of the sympathetic nerves to the pancreas inhibits insulin secretion. The inhibition is produced by released norepinephrine acting on α2-adrenergic receptors. * However, if α-adrenergic receptors are blocked, stimulation of the sympathetic nerves causes increased insulin secretion mediated by β2-adrenergic receptors.

Answer 1206

* Although B cells respond to stimulation with hypertrophy like other endocrine cells, they become exhausted and stop secreting (B cell exhaustion) when the stimulation is marked or prolonged. * For example, diabetes can be produced in animals with limited pancreatic reserves by anterior pituitary extracts, growth hormone, thyroid hormones, or the prolonged continuous infusion of glucose alone. The diabetes precipitated by hormones in animals is at first reversible, but with prolonged treatment it becomes permanent.

Answer 1207

* In pancreatic A cells, it is processed primarily to glucagon and major proglucagon fragment (MPGF). * In lower intestinal and brain L cells, it is processed primarily to glicentin, a polypeptide that consists of glucagon extended by additional amino acid residues at either end, plus glucagon-like polypeptides 1 and 2 (GLP-1 and GLP-2). * Some oxyntomodulin is also formed, and in both A and L cells, residual glicentin-related polypeptide (GRPP) is left. * Glicentin has some glucagon activity. GLP-1 and GLP-2 have no definite biologic activity by themselves. * However, GLP-1 is processed further by removal of its amino-terminal amino acid residues and the product, GLP-1 (7–36), is a potent stimulator of insulin secretion that also increases glucose utilization.

Answer 1208

* Glucagon is glycogenolytic, gluconeogenic, lipolytic, and ketogenic. * In the liver, it acts via Gs to activate adenylyl cyclase and increase intracellular cAMP. This leads via protein kinase A to activation of phosphorylase and therefore to increased breakdown of glycogen and an increase in plasma glucose. * However, glucagon acts on different glucagon receptors located on the same hepatic cells to activate phospholipase C, and the resulting increase in cytoplasmic Ca²⁺ also stimulates glycogenolysis. * Protein kinase A also decreases the metabolism of glucose-6-phosphate by inhibiting the conversion of phosphoenolpyruvate to pyruvate. * It also decreases the concentration of fructose 2,6-diphosphate and this in turn inhibits the conversion of fructose 6-phosphate to fructose 1,6-diphosphate. * The resultant buildup of glucose-6-phosphate leads to increased glucose synthesis and release.

Answer 1209

* It increases gluconeogenesis from available amino acids in the liver and elevates the metabolic rate. * It increases ketone body formation by decreasing malonyl-CoA levels in the liver. * It has lipolytic activity, leads in turn to increased ketogenesis * The calorigenic action of glucagon is not due to the hyperglycemia per se but probably to the increased hepatic deamination of amino acids.

Answer 1210

* Glucagon has a half-life in the circulation of 5–10 min. * It is degraded by many tissues but particularly by the liver. Because glucagon is secreted into the portal vein and reaches the liver before it reaches the peripheral circulation, peripheral blood levels are relatively low. * The rise in peripheral blood glucagon levels produced by excitatory stimuli is exaggerated in patients with cirrhosis, presumably because of decreased hepatic degradation of the hormone.

Answer 1211

* Secretion is increased by hypoglycemia and decreased by a rise in plasma glucose. * Pancreatic B cells contain GABA, and evidence suggests that coincident with the increased insulin secretion produced by hyperglycemia, GABA is released and acts on the A cells to inhibit glucagon secretion by activating GABAA receptors. * The GABAA receptors are Cl^– channels, and the resulting Cl^– influx hyperpolarizes the A cells.