Physiology Flashcards
What is the definition of osmosis?
The diffusion of solvent molecules into a region in which there is a higher concentration of solute to which the membrane is permeable
What is the definition of osmotic pressure?
The excess pressure required to maintain an osmotic equilibrium between a solution and the pure solvent seperated only to the solvent
What does the Van’t Hoff equation describe?
Osmotic Pressure
P = (nRT) / V
P - osmotic pressure
n - number of particles into which the substance dissociates
R - universal gas content, which is 0.082
T - absolute temperature
V - volume
In terms of proportionality, what does the Van’t Hoff equation mean?
Osmotic pressure is directly proportional to it’s absolute temperature, and at a constant temperature, it is directly proportional to the solute concentration
What is osmolarity?
The number of osmoles of solute per litre of solution.
What affects the osmolarity?
It depends on the volume of the solution, and therefore on the temperature and pressure of the solution
What is osmolality?
The number of osmoles of solute per kilogram of solvent
What affects osmolality?
Osmolality depends on the mass of the solvent which is independent of temperature and pressure
What is an osmole?
The amount of substance which must be dissolved in order to produce Avogadro’s number of particles (6.0221 x 10^23)
What is tonicity?
The osmotic pressure between two compartments, and is related to the difference in the concentration of ‘effective’ osmoles between them
What are effective osmoles?
Those substances which are unable to penetrate the membrane between compartments and therefore they are effective in their contribution to osmotic pressure
What are ineffective osmoles?
Substances which are able to equilibrate between compartments, and that are therefore unable to contribute to the osmotic pressure gradient
What is the reflective coefficient?
A measure of how permeable a membrane is to a given solute, where it equals 0 for a perfectly permeable membrane and 1 for a membrane which is perfectively selective
What is an isotonic solution?
Solution separated by a membrane that have equal osmolality on either side so there is no osmotic pressure and they are therefore isotonic
Describe how the movement of fluid between capillaries and tissues is governed by the balance of the hydrostatic pressure and the orthostatic pressure
- If the capillary hydrostatic pressure and blood oncotic pressure are equal, no net fluid movement occurs
- When capillary hydrostatic pressure is higher than oncotic pressure, blood is ultrafiltered out of the capillary and into the tissues
- When oncotic pressure is higher than intravascular hydrostatic pressure, tissue oedema fluid should be attracted back into the circulation
What is the Starling principle?
Hydrostatic pressure is higher than oncotic pressure in the post-arteriolar capillary segments, but as the pressure in the capillary decreases along its length, oncotic pressure ‘wins’ and attracts some of the ultrafiltered water back into the capillaries
On a basic general level, how are body water compartments measured?
Using indicator diluting techniques
Following equilibrium of the indicator into the compartment of interest, the blood level of the indicator can be measured
The volume of distribution of the indicator can then be calculated:
Volume of the compartment = dose of marker / concentration of marker
What are the features that make an ideal indictator to measure body water compartments?
- Safe
- Not metabolised or rapidly excreted
- confined to the compartment of interest
- not prone to changing the distribution of fluids within the compartment
What indicators can be used to measure
1. Total body water
2. Extracellular fluid
3. Plasma volume
4. Blood volume
- TBW - radioactive tritium
- ECF - bromine-82 or mannitol
- Plasma - albumin tagged with evans blue
- Blood - 53Cr labelled red cells
What is the volume of total body water and percentage of this of total body mass?
42L (60% of total body mass in men, 50% in women)
How does the total body water change in obesity?
The total body water is larger but the proportion of total body mass in less as adipose tissue is only 10-20% water
What is the volume of intracellular fluid and precentage of total body mass?
23.1L (33% total body mass)
This volume is regulated by the movement of free water
What is the volume of extracellular fluid and percentage of total body mass?
18.9L (27% total body mass)
This volume is regulated by the movement of sodium
What makes up extracellular fluid?
- plasma volume (2.8L)
- interstitial and lymph fluid
- dense connective tissue and bones
- adipose tissue
Intravascular Fluid
1. % of total body mass
2. % of total fluid
3. volume
Intravascular Fluid
* 4.5% total body mass
* 7.5% total fluid
* 3.15L
Blood Volume
1. % of body mass
2. % of total fluid
3. volume
Blood Volume
* 7% of total body mass
* 12% of total fluid
* 5L
Interstitial Fluid
1. % of body mass
2. % of total fluid
3. volume
Interstitial Fluid
* 12% of total body mass
* 20% of total fluid
* 8.4L
What is the volume of transcellular fluid and percentage of total body mass?
1050ml (1.5% total body mass)
Fluid formed by the secretory activity of cells
What makes up transcellular fluid?
- synovial fluid
- CSF
- aqueous humour
- bile
- bowel contents
- peritoneal fluid
- pleural fluid
- urine in the bladder
What is Fick’s Law of Diffusion?
The rate of diffusion is proportional to concentration and surface area
How come water can diffuse across the lipid bilayer despite it being very hydrophobic?
- 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
Why does the thinness of the lipid bilayer affect diffusion?
Because diffusion rate in inversely proportional to the thickness of the membrane
What affects the water permeability of cell membranes?
The presence of embedded proteins and lipids which change the membrane properties (aquaporins)
What is the main mechanism that determines the balance of volume between the intracellular and extracellular compartments?
The equilibrium of osmolality of the compartments, therefore the most important osmotic agent is extracellular sodium, which is under tight regulation
Why is intracellular water important?
- it acts as a solvent
- its presence is essential for enzyme function
- it acts as a reagant itself
How is the volume of intracellular water determined?
- 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
What does the Gibbs-Donnan effect describe?
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
What is the concentration of total body sodium and how is it distributed?
60mmol/Kg
70kg man - 4200mmol
ECF - 50% total sodium
ICF - 5% total sodium
How does sodium move between the intravascular and interstitial fluid?
Due to the Gibbs-Donnan effect
How is sodium concentration inside the cell kept artificially low?
By the action of the Na+/K+ATPase, which exchanged 3 sodium atoms for every two potassium
What is the concentration of total body potassium and how is it distributed?
40mmol/Kg
70kg man - 2800mmol
ICF - 90%
ECF - 2%
Bone - 8%
How does potassium move between intravascular, interstital and intercellular fluid?
- 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
What is the concentration of total body calcium and how is it distributed?
360mmol/kg
70kg man - 25mol
>99% is stored in bone
ECF - 30mmol
Intracellular calcium is minimal but it is an important secondary messenger
How does calcium move between intravascular, interstital and intercellular fluid?
- 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
What is the concentration of total body magnesium and how is it distributed?
15mmol/Kg
70kg male - 1050mmol
60% is in bone
39% is intracellular
1% is ECF
How does magnesium move between intravascular, interstital and intercellular fluid?
- magnesium moves freely between ECF
- magnesium enters cells freely
- intracellular magnesium is bound to ATP, cell wall lipids and many various enzymes
What is the resting membrane potential?
The voltage (charge) difference between the extracellular and intracellular fluid when the cell is at rest
What are the mechanisms responsible for the resting membrane potential?
- 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)
What is the Nernst potential for each ion?
The transmembrane potential difference generated when that ion is at electrochemical equilibrium
What value is the normal resting potential?
The net charge of the intracellular side of the cell is -70 - -90mV
What is the Nernst equation?
If you account the below as constants you will get:
Vk = -60mV log10 x (Kin - Kout)
What is the Nernst potential for:
K+
Cl-
Na+
Ca2+
K+ -94mV
Cl- -80mV
Na+ +60mV
Ca2+ +130mV
What is the Goldman-Hodgkin-Katz equation?
Most things are pretty constant so it basically equals out as the Nernst equation (just potassium)
What is the threshold potential of a neuronal membrane?
The transmembrane potential required to produce depolarisation of the membrane =
-55mV
What is the all-or-nothing effect?
The finding that a subthreshold stimulus will produce no response, whereas a suprathreshold stimuli will produce an identical and maximal response.
What cell process occurs during depolarisation?
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)
What cell process occurs during repolarisation?
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
How does propagation of the action potential along a neuron occur?
Because the current generated locally by depolarization changes the transmembrane potential in adjacent areas of membrane, also depolarizing it
What are the factors which affect neuronal conduction?
- 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
What is ‘undershoot’ or afterhyperpolarisation?
Why does it happen?
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
What is an axons capacitance?
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
What is axial resistance?
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
What is saltatory conduction?
- 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
What is synaptic neurotransmission?
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.
What is a synapse?
A narrow (20-30nm) junction between two neurons
What are neurotransmitters and what are some of their shared properties?
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
What are some excitatory neurotransmitters?
Glutamate
Dopamine
Noradrenaline
Acetylcholine (nicotinic receptors)
What are some inhibitory neurotransmitters?
GABA
Serotonin
Acetylcholine (muscarinic receptors)
Describe synaptic neurotransmission on a basic level
- 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
What are the proteins that calcium targets in synaptic neurotransmission? what are the responsible for?
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
What are the two main things neurotransmitters do in the synapse?
- 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
How is the neurotransmitter cleared from the synaptic cleft?
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
What is the mechanism of contraction of skeletal vs smooth vs cardiac muscle?
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
What is the mechanism of relaxation of skeletal vs smooth vs cardiac muscle?
Skeletal and cardiac muscle
calcium dissociation away from tropomyosin and troponin
Smooth muscle
dephosphorylation of myosin light chains by myosin light chain phosphatase
What is the role of calmodulin in skeletal vs smooth vs cardiac muscle?
Skeletal muscle
minor
Smooth muscle
central
Cardiac muscle
regulatory
What is a sarcoplasmic reticulum?
A specially organised organelle that mainly plays the role in coordinating calcium traffic
What is a motor unit of muscle?
It consists of a large anterior horn cell, its motor axon, and the skeletal muscle fibres innervated by that axon
How does smooth muscle contract?
- 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
How does smooth muscle relax?
- 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
What does the reflex arc consist of?
A sense organ, an afferent neuron, one of more synapses of a central integrating system, an efferent neuron and an effector
Where do the afferent and efferent fibres travel through the spinal cord?
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.
What are the types of potentials created in the reflex arc.
- 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
What is an adequate stimulus?
The stimulus that triggers a reflex. It is often very precise
What type of neurons are the efferent nerves in the reflex arc?
alpha motor neurons
What is the final common pathway?
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.
What are monosynaptic and polysynaptic reflexes?
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
What is the stretch or myotactic reflex?
When a skeletal muscle with an intact nerve supply is stretched, it contracts. This response is called the stretch reflex.
What is the following in the stretch reflex:
- stimulus
- response
- sense organ
- neurotransmitter
- give an example of the stretch reflex
- 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
What are the three essential parts of a muscle spindle?
- A group of specialised intrafusal muscle fibres with contractile polar ends and a non-contractile centre
- Large diameter myelinated afferent nerves originating in the central portion of the intrafusal fibres
- Small diameter myelinated efferent nerves supplying the polar contractile regions of the intrafusal fibres
How are muscle spindles linked with proprioception?
Changes in muscle length are associated with changes in joint angle; thus muscle spindles provide information on position - proprioception
Where will you find muscle spindles?
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
What are the two types of intrafusal muscle fibres? Tell me a little bit about them
- 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
What are the two kinds of sensory endings in each spindle? What do they measure?
- 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)
What nerves supply muscle spindles?
Gamma - motor neurons
How do the afferent nerves of the muscle spindles connect to the muscle they move?
Ia fibres end directly on motor neurons supplying the extrafusal fibres of the same muscle
In reflexes, what is the reaction time and the central delay? Give values for both
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
What scenario takes place that stops the muscle spindles from firing?
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.
What is the difference between alpha motor neuron and gamma motor neuron stimulation?
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.
How are the gamma motor neurons regulated?
From descending tracts from a number of areas of the brain that also control alpha motor neurons
What is reciprocal innervation?
When a stretch reflex occurs, the muscles that antagonise the muscle involved relax. This is called reciprocal innervation
How does reciprocal innervation take place?
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
What is the inverse stretch reflex?
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.
What is the receptor for the inverse stretch reflex?
How does it work?
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.
What is muscle tone?
What does it mean if the muscle is:
* flaccid/hypotonic
* hypertonic
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
What is the clasp-knife effect, otherwise known as lengthening reaction?
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
How are polysynaptic reflex different from monosynaptic reflexes?
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
What is the withdrawal reaction?
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
What is the crossed extensor response?
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.
What is irradiation of the stimulus?
The spread of excitatory impulses up and down the spinal cord to more and more motor neurons
Withdrawal reflexes are prepotent, what does this mean?
They preemt the spinal pathways from any other reflex activity taking place at that moment
What is after-discharge with reflexes?
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
What is the sensory pathway of vision?
- 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.
What is the pathway that mediates the pupillary light reflex and eye movements?
Some ganglion cell axons bypass the lateral geniculate to project directly to the pretactal area.
How does the retina transmit information to the lateral geniculate body? How does this link with the structure of the lateral geniculate body?
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.
Where does the lateral geniculate nucleus get its information from?
Approx 10-20% from the retina. Major inputs also come from the visual cortex and other brain regions
What are the cell types in the retinal ganglion cells and where do they get their information from?
- 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
What are the two pathways from the lateral geniculate pathway to the primary visual cortex? Which P cells and M cells travel in each pathway?
- 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
What are the following lesions called and where is the lesion?
- 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
Label where these areas of the occipital region get their sensory nerves from
What does the reticular formation include?
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
What is the reticular activating system?
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
Why is the reticular activating system non-specific?
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
Are the principal afferent and efferent neural pathways to and from the hypothalamus myelinated or unmyelinated?
Unmyelinated
What are some important connections to and from the hypothalamus?
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.
What are the principal hypothalamic regulatory mechanisms?
- 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
For temperature regulation, where are the
1) afferents from
2) integrating areas
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
For catecholamine regulation, where are the
1) afferents from
2) integrating areas
1) Afferents from limbic areas concerned with emotion
2) Integrating areas are dorsal and posterior hypothalamus
For vasopressin regulation, where are the
1) afferents from
2) integrating areas
1) Afferents from osmoreceptors and ‘volume receptors’
2) Integrating areas are supraoptic and paraventricular nuclei
For oxytocin regulation, where are the
1) afferents from
2) integrating areas
1) Afferents from touch receptors in breast, uterus, genitalia
2) Integrating areas are supraoptic and paraventricular nuclei
For TSH regulation, where are the
1) afferents from
2) integrating areas
1) Afferents from temperature receptors in infants and others
2) Integrating areas include paraventricular nuclei and other neighbouring areas
For ACTH regulation, where are the
1) afferents from
2) integrating areas
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
For FSH and LH regulation, where are the
1) afferents from
2) integrating areas
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
For prolactin regulation, where are the
1) afferents from
2) integrating areas
1) Afferents from touch receptors in breasts
2) Integrating areas include arcuate nucleus
For thirst regulation, where are the
1) afferents from
2) integrating areas
1) Afferents are from osmoreceptors and angiotensin II uptake
2) Integrating areas include lateral superior hypothalamus and subfornical organ
For hunger regulation, where are the
1) afferents from
2) integrating areas
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
For sexual behaviour regulation, where are the
1) afferents from
2) integrating areas
1) Afferents from cells sensitive to circulating oestrogen and androgen
2) Integrating areas from anterior ventral hypothalamus plus in the male, piriform cortex
For defense reactions regulation, where are the
1) afferents from
2) integrating areas
1) Afferents from sense organs and neocortex
2) Integrating areas are diffuse, in limbic system and hypothalamus
Where is vasopressin and oxytocin released from?
Posterior pituitary
What are the ascending spinal tracts?
The neural pathways by which sensory information from the peripheral nerves is transmitted to the cerebral cortex.
What sensory modality does the dorsal column-medial lemniscal pathway carry?
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
There are three types of neuron in the dorsal column-medial lemniscal pathway. What are they?
- First order neurons - carry sensory information regarding touch, vibration and proprioception from the peripheral nerves to the medulla oblongata
- 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
- Third order neurons transmit the signals from the thalamus to the ipsilateral primary sensory cortex
There are two types of first order neurons in the DCML pathway, what are they?
- 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
What are the tracts that make up the anterolateral (or ventrolateral) spinothalamic tracts?
- Anterior spinothalamic tract - crude touch and pressure
- Lateral spinothalamtic tract - pain and temperature
What are the three neurons that make up the anterolateral spinothalamic tract and what are their paths?
- 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
What are the spinocerebellar tracts?
The tracts that carry unconscious proprioceptive.
If there is a lesion in the spinal cord of the dorsal column-medial lamniscus tract, what will the symptoms be?
Loss of proprioception and fine touch on the ipsilateral side as it decussates in the medulla
What is Brown-Sequard syndrome and what are the symptoms?
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
The descending motor tracts can be functionally split into two groups. What are they and what do they do?
- 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
What are upper vs lower motor neurons?
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
What are the two pyramidal tracts?
- Corticospinal tract - supplies the musculature of the body
- Corticobulbar tract - supplies the musculature of the head and neck
Tell me about the journey of the corticospinal tract before it reaches the medulla?
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
Once the corticospinal tract reaches the medulla, it splits into two branches. What are these and what do they do?
- 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
What is the path of the corticobulbar tract?
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.
Do the corticobulbar tracts innervate the motor neurons ispilaterally, contralaterally or bilaterally?
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
What are the extrapyramidal tracts responsible for and what are the four tracts?
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
Do all of the four extrapyramidal tracts decussate?
The vestibulospinal and reticulospinal tracts do not decussate, providing ipsilateral innervation.
The rubrospinal and tectospinal tracts decussate, therefore provide contralateral innervation.
Tell me about the vestibulospinal tracts…
How many are there? Where do they come from? What do they control?
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
Tell me about the reticulospinal tracts…
How many are there? What are their functions?
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
What is the path of the rubrospinal tract and what is it’s function?
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
What is the pathway of the tectospinal tract and what is it’s function?
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
If there is a unilateral lesion of the right or left anterior corticospinal tract, symptoms will occur on which side of the body? What would the symptoms be?
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
What is Babinski’s sign?
Extension of the hallux in response to blunt stimulation of the sole of the foot
A unilateral lesion to the hypoglossal nerve (CN XII) will lead to what symptoms in upper motor neuron and lower motor neuron location?
- 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
What is the difference between upper motor neuron and lower motor neuron damage in the facial nerve (CN V)?
- A lesion in the upper motor neuron is forehead sparing
- A lesion in the lower motor neuron includes the forehead
Label the tracts of the spinal cord
Where is the SA and the AV node?
- 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.
How many bundles of atrial fibres that contain Purkinje-type fibres and connect the SA and AV node are there? What are they called?
There are three:
- Anterior
- Middle (tract of Wenckebach)
- Posterior (tract of Thorel)
The AV node connects to the Bundle of His. What are the branches of the Bundle of His, where do they come off and where do they go?
- 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.
What is the histology of Purkinje cells, SA node and AV node?
- 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.
How does the heart ensure conduction only travels down the Bundle of His rather than directly from the atria to the ventricles?
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.
Which side vagus nerve stimulates the SA and AV node? Why?
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.
Connections exist for reciprocal inhibitory effects of the sympathetic and parasympathetic innervation of the heart on each other. What are they?
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.
What property allows individual cardiac fibres to spread depolarisation rapidly?
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.
What are the stages of the cardiac cycle in terms of repolarisation and ion channels? What happens in each one
- 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
What is the conduction rate in the following areas of the heart?
- SA node
- atrial pathways
- AV node
- Bundle of His
- Purkinje system
- Ventricular muscle
What is the pre-potential or pacemaker potential of cardiac rhythmically discharging cells?
Rhythmically discharging cells have a membrane potential that after each impulse, declines to the firing level. Thus, this pre-potential triggers the next impulse.
think ion changes and channels
What brings about the pacemaker potentials in rhythmically discharging cells in the heart?
- At the peak of each impulse, Ik begins and brings about repolarisation.
- Ik 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 Ih 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.
What are the different types of calcium channels that control the pacemaker potentials in cardiac cells?
There are two types of calcium channels in the heart.
- T (transient) channels - the calcium current (ICa) due to opening of the T channels completes the prepotential.
- L (long-lasting) channels - the calcium current (ICa) due to opening of the L channels produces the impulse
How is the action potential graph of rhythmically discharging cells different from the other parts of the conducting system? and why?
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.
What happens to the SA and AV node when the cholinergic vagal fibres to nodal tissues are stimulated?
- 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 IKAch slows the depolarising effect if Ih.
- 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.
What happens to the SA and AV node when the sympathetic cardiac nerves are stimulated?
- It speeds the depolarising effect of Ih, 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 ICa and the rapidity of the depolarisation phase of the impulse
What is the spread of excitation through the heart?
- 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.
Because conduction of the AV node is slow, there is an AV nodal delay before excitation spreads to the ventricles. How long is this delay?
0.1 seconds
How long does it take for the wave of depolarisation to spread from the top of the septum to all parts of the ventricles through the speedy Purkinje fibres?
0.08 - 0.1 seconds
What are the different types of electrode recordings you can have in an ECG?
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).
What is the Einthoven triangle?
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.
How does depolarisation and repolarisation of each electrode affect an ECG?
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.
What action creates the following waves in an ECG?
* P wave
* QRS complex
* T wave
* U wave
- 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
What are the bipolar leads of an ECG? What do they represent?
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
What are the durations and events that occur during the following intervals in an ECG?
* PR interval
* QRS duration
* QT interval
* ST interval
- 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
What are the unipolar leads of an ECG?
Inclduing what an augmented limb lead is pls
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.
Where can unipolar leads be placed apart from the classic places?
They can be placed at the tips of catheters and inserted into the oesophagus or the heart
What aspects of the heart does aVR look at and therefore what should its normal pattern be?
aVR looks at the cavities of the ventricles and all waves should have negative deflections because all the pathways lead away from it
What aspects of the heart does aVL and aVF look at and therefore what should its normal pattern be?
aVL and aVF look at the ventricles and the deflections are either positive or biphasic because the pathways lead towards them
What aspects of the heart does V1 and V2 look at and therefore what should its normal pattern be?
- 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.
What aspects of the heart does V4-V6 look at and therefore what should its normal pattern be?
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)
What is the cardiac axis?
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.
How can the cardiac axis be calculated from two limb leads?
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.
What is the normal direction of the mean QRS axis? What is left and right axis deviation?
-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
Why does your heart beat faster in inspiration and slower in expiration?
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.
What is complete heart block? What are the two areas where there may be disease that causes this?
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)
What is the average heart rate for patients with 1) AV nodal heart block and 2) Infranodal heart block. Why?
- In patients with AV nodal block, the remaining nodal tissue becomes the pacemaker and the rate of the idioventricular rhythm is approx 45 bpm.
- 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)
What are the types of incomplete heart block?
- 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.
What happens in bundle branch block?
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
What are the types of left bundle branch block?
- 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
What is increased automaticity of the heart?
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.
What happens if an irritable ectopic focus discharges?
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)
What happens during re-entry pathways?
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
What is the atrial rate in atrial flutter? How does it normally happen?
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.
What are the consequences of atrial arrhythmias?
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.
What changes do you see on an ECG in ventricular arrhythmias?
- 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.
What is Torsades de Pointes?
A form of ventricular tachycardia where the QRS morphology varies
What happens to the electrical activity in the heart in VF?
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.
What is the vulnerable period for VF?
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.
Why is long QT syndrome important?
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.
What can cause long QT syndrome? Roughly, how do genetics cause it?
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
What is Wolff-Parkinson-White syndrome?
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.
What does the ECG look like in WPW?
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.
Why do the paroxysmal atrial tachycardias happen in WPW?
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
What are the genetic changes that cause WPW?
There is a mutation in a gene that codes for AMP-activated protein kinase
What is Lown-Ganong-Levine syndrome?
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.
What happens in the cardiac cycle in terms of filling, volume and pressure?
- Atrial systole
- Isovolumetric ventricular contraction
- Ventricular ejection
- Isovolumetric ventricular relaxation
- Ventricular filling
What happens late in diastole during ventricular filling?
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.
How much of the ventricular filling occurs during diastole?
Around 70%
What happens during atrial systole?
- 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.
What happens during isovolumetric ventricular contraction?
- 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.
What happens during ventricular ejection?
- 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.
How long does isovolumetric ventricular contraction last for?
0.05 seconds
What are the pressures in the aorta and pulmonary veins?
What are the peak pressures in the left and right ventricles?
Aorta - 80mmHg, 10.6kPa
Pulmonary artery - 10mmHg
Left ventricle - 120mmHg
Right ventricle - 25mmHg
What is the volume of blood ejected by each ventricle per stroke at rest?
What is the end-diastolic ventricular volume and therefore the end-systolic ventricular volume.
Volume of blood ejected - 70-90mL
End-diastolic ventricular volume - 130mL
End-systolic ventricular volume - 50ml
What is the ejection fraction?
The percentage of the end-diastolic ventricular volume that is ejected with each stroke, approx 65%
What happens during protodiastole? How long does it last?
- 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.
What happens during isovolumetric ventricular relaxation?
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.
Which side of the heart contracts first?
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.
How does inspiration and expiration affect the timing of the valve closures?
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.
How does the length of systole and diastole change during tachycardia?
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
Why is the length of diastole important?
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.
What is the total electromechanical systole (QS2)?
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.
What is the left ventricular ejection time (LVET)?
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.)
What is the preejection period (PEP)?
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.
In young adults, what speed does the pulse wave travel through:
- the aorta
- the large arteries
- small arteries
- Aorta - 4m/s
- Large arteries - 8m/s
- Small arteries - 16m/s
What is the Corrigan or water-hammer pulse a sign of? Why does it happen?
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.
What happens from points a-d in this normal pressure-volume loop of the left ventricle?
- 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.
In recording of jugular pressure, what is the a wave, c wave and v wave?
- 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
What happens to the JVP during inspiration?
Venous pressure falls during inspiration as a result of the increased negative intrathoracic pressure and rises again during expiration.
What causes the first, second, third and fourth(!) heart sound?
- 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.
What is the length and frequency of the first, second and third heart sounds?
- 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
When would you hear a murmur in aortic stenosis or pulmonary regurgitation?
Systolic murmurs occur in aortic stenosis and pulmonary regurgitation
When would you hear a murmur in aortic regurgitation or pulmonary stenosis?
During diastole
How do you calculate flow? How is this related to the vascular system and the effective perfusion pressure?
Flow = Pressure/Resistance
Therefore, flow in any portion of the vascular system is therefore equal to the effective perfusion pressure/resistance.
What is the effective perfusion pressure?
The mean intraluminal pressure at the arterial end minus the mean pressure at the venous end
What are the units of resistance?
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.
How can you measure blood flow?
Usually with Doppler flow meters
What is laminar blood flow?
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
What is Reynold’s number?
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
Above what Reynolds number is blood flow usually turbulent?
Flow is usually not turbulent if Re is less than 2000.
When Re is more than 3000, turbulence is almost always present
What is the difference between velocity and flow? and what is their relationship between each other and the area of a conduit?
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.
What is the Poiseuille-Hagen Formula?
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:
How does flow vary with the radius of a vessel? How does the radius need to change to double flow
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
How does resistance vary with radius? What happens to the resistance when the radius is doubled?
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
How does the viscosity of plasma and whole blood compare to water?
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
What is the Fahraeus-Lindqvist effect?
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.
Why does the Fahraeus-Lindqvist effect work?
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.
What is the critical closing pressure?
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 intralumincal pressure falls below the pressure exerted by neighbouring tissues.
The pressure at which flow ceases if called the critical closing pressure.
What is Laplace’s Law?
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)
How does Laplace’s law effect blood vessels?
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.
How is Laplace’s law linked with aneurysms and dilated cardiomyopathy?
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
Why are veins capitance vessels?
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
What is autoregulation?
The capacity of tissues to regulate their own blood flow is referred to as autoregulation
At rest, what percentage of the circulating blood volume is in:
- the systemic veins
- the heart cavities
- low-pressure pulmonary circulation
- the aorta
- the arteries
- arterioles
- capillaries
Systemic veins - 50%
Heart cavities - 12%
Low pressure pulmonary circulation - 18%
Aorta - 2%
Arteries - 8%
Arterioles - 1%
Capillaries - 5%
What is the myogenic theory of autoregulation?
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
What is the metabolic theory of autoregulation?
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
What are the metabolic changes that produce vasodilation?
In most tissues, decreases in O2 tension and pH.
These changes cause relaxation of the arterioles and precapillary sphincters
How does a fall in O2 tension produce vasodilation?
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
How do increases in temperature dilate the vessels?
It exerts a direct vasodilator effect, and the temperature rise in active tissues (due to the heat of metabolism) may contribute to vasodilation
How does hyperkalaemia cause vasodilation?
It accumulates locally, and has demonstrated dilator activity secondary to the hyperpolarisation of vascular smooth muscle cells.
How is NO synthesised?
From argnine in a reaction catalysed by nitric oxide synthase (NOS)
What are the three isoforms of NO synthase (NOS) and where are they found?
NOS 1 in the nervous system
NOS 2 in macrophages and other immune cells
NOS 3 found in endothelial cells
What activates NOS 1, NOS 2 and NOS 3?
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
What local factors act independently and dependently on the epithelium to cause vasodilation?
Independently
* Adenosine
* ANP
* Histamine via H2 receptors
Act on endothelium
* Acetylcholine
* Histamine via H1 receptors
* Bradykini
* Vasoative intestinal peptide (VIP)
* Substance P
What causes the release of NO for physiological vasodilation?
- 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.
What is the function of Endothelin-1?
It is a potent vasoconstrictor.
How many endothelins are there? Where are they found?
- 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.
How is endothelin-1 secreted?
Small amounts are secreted into the blood, but for the most part, they are secreted locally and act in a paracrine fashion
What are the two different endothelin receptors? What do they mediate?
The ETA receptor, which is specific for endothelin-1, is found in many tissues, and mediates the vasoconstriction produced by endothelin-1
The ETB 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.
What neurohumoral agents affect systemic regulation?
- The vasodilator regulators include kinins, VIP, and ANP
- Circulating vasoconstrictor hormones include vasopressin, noradrenaline, adrenaline and angiotensin II
What are the two related kinins and how are they related?
Kallidin can be converted to bradykinin by aminopeptidase.
How are both kinins metabolised and inactivated?
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
What precursor proteins are the kinins formed from? Which proteases cause this happen?
- 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)
What are the actions of the kinins?
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
What are baroreceptors and where are they?
They are stretch receptors in the walls of the heart and the blood vessels.
Where are the baroreceptors that monitor the arterial circulation?
The carotid sinus and the adventitia of the aortic arch
The receptors in the low-pressure part of the circulation are referred to collectively as the cardiopulmonary receptors. Where are they?
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.
What and where is the carotid sinus?
It is a small dilatation of the internal carotid artery just above the bifurcation of the common carotid into external and internal carotid branches
Where do the afferent nerve fibers from the carotid sinus and the aortic arch go?
- 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
What stimulates baroreceptors and what is the path of the nerves once they’re stimulated?
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.
What does increased baroreceptor discharge inhibit and excited and what is the result of this?
- 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.
Are baroreceptors more sensitive to pulsatile pressure or constant pressure? What does this mean?
- 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.
At normal BP levels, how does baroreceptor firing change during systole and diastole?
During systole, a burst of action potentials appear in a single baroreceptor fibre
There are few action potentials in early diastole
How does baroreceptor firing change at lower blood pressures?
The overall firing rate is considerably reduced.
What is the threshold for eliciting baroreceptor activity in the carotid sinus nerve? At what pressure does maximal activity of baroreceptors occur?
The threshold for eliciting activity in the carotid sinus nerve is approx 50mmHg
Maximal activity occurs at approximately 200mmHg
What is baroreceptor resetting and when does it occur?
In chronic HTN, the baroreceptor reflex mechanism is ‘reset’ to maintain an elevated rather than a normal blood pressure.
Baroreceptors are very important in short-term control of arterial pressure. What does this allow us to do?
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.
What is neurogenic HTN?
A long-term change in blood pressure resulting from loss of baroreceptor reflex control is called neurogenic HTN
What are the two types of stretch receptors in the atria?
- 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
What increases and decreases the discharge of type B baroreceptors in the atria?
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.
What are the systemic outcomes of activation of the Type B atrial stretch receptors?
Vasodilation and a fall in blood pressure. However, the heart rate is increased rather than decreased
When are baroreceptors in the endocardial surfaces of the ventricles activated and what is the result of this?
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.
What is a Valsava maneuver? What are some examples?
It is forced expiration against a closed glottis.
Valsava maneuvers occur regularly during cough, defecation and heavy lifting.
What happens to the blood pressure and baroreceptors during a Valsalva maneuvre?
- 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.
What is the Bezold-Jarisch reflex?
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
Where are peripheral arterial chemoreceptors and what are they activated by?
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.
Where do chemoreceptors exert their main effects?
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.
How does hypoxia add to the effect of chemoreceptor activation?
Hypoxia also produces hyperpnea and increased catecholamine secretion from the adrenal medulla, both of which produce tachycardia and an increase in cardiac output.
How does haemorrhage cause chemoreceptor stimulation?
It decreases blood flow to the chemoreceptor stimulation due to decreased blood flow to the chemoreceptors and consequent stagnant anoxia of these organs
What are Mayer waves and Traube-Hering waves? Which one is associated with chemoreceptor discharge?
- 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.
How does moderate hyperventilation affect the vessels and CO2 in the blood?
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
How does a rise in arterial pCO2 affect the body via baroreceptors and chemoreceptors?
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.
Exposure to high concentrations of CO2 affects the vessels and BP how?
There is marked cutaneous and cerebral vasodilation, but vasoconstriction occurs elsewhere and usually there is a slow rise in BP.
What is renin? What is it’s action?
An acid protease secreted by the kidney into the bloodstream.
The enzyme acts in concert with ACE to form angiotenin II
What is the chemical make up of renin?
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.
Like other hormones, renin is synthesised as a large pre-prohormone. What is the pre-prohormone?
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.
Where is prorenin secreted and converted to renin?
- 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
What is the half-life of renin in the circulation?
80 minutes or less
Where is angiotensinogen synthesised?
It is synthesised in the liver with a 32-amino-acid signal sequence that is removed in the endoplasmic reticulum.
What increases the circulating angiotensinogen level?
Glucocorticoids
Thyroid hormones
Oestrogens
Several cytokines
Angiotensin II
What is angiotensin converting enzyme and what does it do?
- 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
Where is ACE found and where does the conversion from angiotensin I to angiotensin II take place?
- 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.
ACE is an ectoenyme that exists in two forms. What are they? What is the difference?
- 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.
How is angiotensin II metabolised? Is it quick?
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.
What is the function of angiotensin I?
It appears only to function solely as the precursor of angiotensin II and does not have any other established action
What is the function of angiotensin II?
- 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
Does angiotensin II cross the blood brain barrier?
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.
In addition to the system that generates circulating angiotensin II, many different tissues contain independent renin-angiotensin systems, apparently generating angiotensin II for local use. Tell me about these.
- 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
There are at least two classes of angiotensin II receptors. Tell me about them.
- 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.
AT1 receptors in the arterioles and the AT1 receptors in the adrenal cortex are regulated in opposite ways. What are these?
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.
The renin in the kidney extracts and the bloodstream is produced by what cells? Where are they? and where is renin found inside them?
- 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
Where is the macula densa in the kidney? What is it and what does it mark?
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
What constitutes the juxtaglomerular apparatus?
The lacis cells, the JG cells and the macula densa consistute the juxtaglomerular apparatus.
What are the stimulatory and inhibitory factors that affect renin secretion?
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
What the principal conditions that increase renin secretion?
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
What are the three methods of measuring cardiac output?
- Doppler combined with echo
- Direct Fick’s method
- Indicator dilution method
What is the Fick’s principle in relation to cardiac output? How can we use it to work out the output?
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
How can the indicator dilution technique be used to measure cardiac output?
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.
A popular indicator dilution technique is thermodilution. How does this work?
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
What is the stroke volume in a resting man of average size in the supine position?
The amount of blood pumped out of the heart per beat (stroke volume) is about 70mL from each ventricle.
What is the cardiac output in a resting supine man?
The output of the heart per unit of time (cardiac output) is about 5L/minute
What is the cardiac index? What is its average volume?
The output per minute per square meter of body surface averages 3.2L
Name some factors that have no change on cardiac output?
Sleep
Moderate changes in environmental temperature
Name some situations that increase cardiac output?
Anxiety and excitement (50-100%)
Eating (30%)
Exercise (up to 700%)
High environmental temperature
Pregnancy
Adrenaline
Name some factors that decrease cardiac output?
Sitting or standing from lying position (20-30%)
Rapid arrythmias
Heart disease
Predictably, changes in cardiac output that are called for by physiologic condition can be produced by changes in cardiac rate, or stroke volume, or both. What are these things primarily controlled by?
- 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.
What is chronotropic vs inotropic action?
- 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
The force of contraction of cardiac muscles depends on its preloading and afterloading. Explain why?
- 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
The length-tension relationship in cardiac muscle is similar to that in skeletal muscle. What is this?
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.
What is Starling’s law of the heart and the Frank-Starling curve?
‘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
What is heterometric regulation and homometric regulation?
- 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
What limits the extent to which a ventricle can fill?
- 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
What things increase venous return?
- 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
How does the Frank-Starling curve shift when the sympathetic nerves to the heart are stimulated?
Upwards and to the left
Changes in cardiac rate and rhythm affect myocardial contractility? What is this know as and what happens?
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.
How does the postextrasystolic potentiation happen?
- 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
What effect do catecholamies have on the heart and how do they exert it?
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.
What effect do Xanthines and caffiene have on the heart and how do they exert it?
They inhibit the breakdown of cAMP and are predictably positively inotropic.
What effect does digoxin have on the heart and how does it exert it?
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
What things depress myocardial contractility?
Hypercapnia
Hypoxia
Acidosis
Drugs such as procainamide and barbiturates
Heart failure
What are the cardiac differences between untrained individuals and trained athletes?
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.
What is the basal O2 consumption by the myocardium and how is that compared to that of resting skeletal muscle and to that by the beating heart?
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
What increases oxygen consumption by the heart?
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.
What is O2 consumption by the heart primarily determined by?
The intramyocardial tension, the contractile state of the myocardium and the heart rate.
How do you work out ventricular work?
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).
How are the stroke works of the left ventricle and right ventricle different? why?
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.
How do pressure work and volume work cause different changes in O2 consumption? What does this mean in terms of afterload and preload?
- 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.
The principal arterial inflow to the brain is via four arteries. What are they?
Two internal carotid arteries and two vertebral arteries.
The two vertebral arteries unite to form what?
The basilar artery
What arteries form the circle of Willis? Where is it?
The basilar artery and the carotids form the circle of Willis below the hypothalamus
Substances distributed into one carotid artery are distributed where?
Almost exclusively to the cerebral hemisphere on that side.
Normally no crossing over occurs, probably because the pressure is equal on both sides.
On a generic basis, how does venous drainage of the brain happen?
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
What is the blood flow of the:
- liver
- kidneys
- brain
- skin
- skeletal muscle
- heart muscle
- whole body
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
What is the cardiac output as a percentage of whole body of the following:
- liver
- kidneys
- brain
- skin
- skeletal muscle
- heart muscle
- Liver - 27.8%
- Kidneys - 23.3%
- Brain - 13.9%
- Skin - 8.6%
- Skeletal muscle - 15.6%
- Heart muscle - 4.7%
What is the oxygen consumption as a percentage of whole body of the following:
- liver
- kidneys
- brain
- skin
- skeletal muscle
- heart muscle
- Liver - 20.4%
- Kidneys - 7.2%
- Brain - 18.4%
- Skin - 4.8%
- Skeletal muscle - 20.0%
- Heart muscle - 11.6%
Morphologically, what is special about the choroid plexuses?
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.
Morphologically, what are the capillaries in the brain like?
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.
Where are the endfeet of astrocytes and what do they do?
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
Three systems of nerves innervate the cerebral blood vessels. What are they?
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 contrain substance P, neurokinin A, and calcitonin gene-related peptide, which cause either vasodilation or vasoconstriction.
CSF is formed continuously by the choroid plexus in two stages. What are they?
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.
What percentage of brain volume is made up of brain extracellular fluid?
15%
What is the normal lumbar CSF pressure?
70-180mmH2O.
How are CSF pressure and absorption related?
What are some important pressures to remember and why?
- 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.
What situations have to occur for large amounts of CSF fluid to accumulate? What happens because of the blockage?
- 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).
In what type of head injuries is the brain damaged most commonly?
- 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)
What makes up the blood-brain barrier?
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
What molecules penetrate the brain with ease?
Water, CO2 and O2
Lipid-soluble free forms of steroid hormones
What does the penetration of CO2, H+ and HCO3 into the brain effect?
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.
Glucose is the major ultimate source of energy for nerve cells. How does it cross the blood-brain barrier?
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)
A variety of drugs and peptides actually cross the cerebral capillaries but are promptly transported back into blood by what?
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.
What four small areas in or near the brainstem are outside the blood brain barrier? What are there referred to collectively?
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
What is the function of the blood-brain barrier?
- 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
What does Kety’s method measure? How? and what principle does it use?
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)
What are the factors involved in regulating overall cerebral circulation?
- ICP
- Local constriction and dilation of cerebral arterioles
- Mean arterial pressure at brain level
- Viscosity of blood
- Mean venous pressure at brain level
What is the Monro-Kellie doctrine?
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
What happens to the cerebral vessels when the intracranial pressure rises?
The cerebral vessels are compressed.
How does a change in venous pressure effect intracranial pressure and therefore cerebral blood flow? How is this helpful?
- 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.
Give some examples of when the venous pressure would change intracranial pressure in every day life?
- 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
In the brain, autoregulation maintains a normal cerebral blood at what arterial pressures?
65-140 mm Hg
What is the role of vasomotor and sensory nerves in the innervation of large cerebral blood vessles?
- 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
How is glutamate involved in removal of ammonia from the brain?
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
Where do the two coronary arteries supplying the myocardium arise from?
From the sinuses behind two of the cusps of the aortic valve at the root of the aorta.
Where does most of the coronary venous blood return to the heart?
- 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
What happens to the cardiac blood vessels when it contracts?
They are compressed
When does blood flow occur in the arteries supplying the subendocardial portion of the left ventricle and why?
- 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.
How does left ventricular coronary flow change in tachycardia and why?
Because diastole is short when the heart rate is high, LV coronary flow is reduced during tachycardia
How is coronary flow in the right ventricle and both atria effected by systole and why?
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
Where is the most common site of MI and why?
Because no blood flow occrus 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
How is blood flow to the left ventricle effected by aortic stenosis and why?
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
How do conditions like heart failure effect coronary blood flow and why?
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.
What is the pressure in the aorta, left ventricle and right ventricle during systole and diastole?
What is coronary flow at rest? What percentage of cardiac output is this?
About 250mL/min (5% of the cardiac output)
How is lipoprotein(a) associated with atherosclerosis?
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
What are the chemical factors associated with coronary flow?
- Lack of O2
- Increased local concentrations of CO2, H+, K+, lactate, prostaglandins, adenine nucleotides and adenosine
What are the neural receptors are associated with coronary circulation?
- The coronary arterioles contain α-adrenergic receptors, which mediate vasoconstriction
- The coronary arterioles also contain β-adrenergic receptors, which mediate vasodilation.
How does noradrenaline effect coronary circulation? What happens if its discharge is blocked?
- 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.
What happens to the coronary flow if BP drops and why?
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.
What is the white reaction in skin? Why does it happen?
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.
What is the triple response in skin?
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
How does local anaesthetic in the skin affect the triple response?
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.
What causes the triple reaction in skin?
- 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
What is reactive hyperemia? How does it happen?
- 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.
How does the skin respond to temperature and how does this relate to how it responds to other reflexes?
- 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.
What constricts and dilates cutaneous blood vessels?
- 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.
In a resting adult how much blood per minute do the kidneys receive? What is this as a percentage of the cardiac output?
1.2 - 1.3L of blood per minute
Just under 25% of cardiac output
What does the renal plasma flow represent?
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.
What is used to measure the effective renal plasma flow? How does this happen? What is its usual value?
- 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.
From the renal plasma flow, how can you calculate the renal blood flow?
Renal blood flow is the renal plasma flow multiplied by 1 divided by 1 minus the haematocrit
The pressure in the glomerular capillaries has been found to be considerably less than predicted. What is it?
- 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.
How is renal blood flow regulated?
- 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
What does stimulation of the renal nerves do?
- 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
What does strong stimulation of the sympathetic noradrenergic nerves to the kidneys cause? and how?
- 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.
When systemic blood pressure falls, what happens to the renal circulation and how?
When systemic blood pressure falls, the vasoconstrictor response produced by decreased discharge in the baroreceptor nerves includes renal vasoconstriction
How does renal blood flow stay relatively constant?
When the kidney is perfused at moderate pressures, the renal vascular resistance varies with the pressure so that renal blood flow is relatively constant
What prevents renal autoregulation and in what situations does autoregulation take place?
Renal autoregulation is present in denervated and in isolated, perfused kidneys but is prevented by the administation of drugs that paralyse vascular smooth muscle.
What produces renal autoregulation?
- 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.
What is the main function of the renal cortex? How does this effect oxygen uptake?
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.
What is the blood flow of the medulla of the kidney compared to the cortex? Give me numbers please.
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
What affects the volume of oxygen delivered to the systemic vascular bed per minute?
The product of the cardiac output and the arterial oxygen concentration.
What does the oxygen delivery to a particular tissue depend on?
- 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
What determines the amount of O2 in the blood?
- The amount of dissolved O2
- The amount of haemoglobin in the blood
- The affinity of the Hb for O2
What is the structure of Hb?
- 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.
How does Hb get oxygenated? How quickly does it happen?
- 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.
The quaternary structure of Hb determines its affinity for O2. How?
- 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.
What does the oxygen-haemoglobin dissociation curve show?
- 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.
How is the dissolved O2 concentration related to the PO2 and the oxygen saturation? What are the values at 100% O2. How does it change?
- 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
How saturated is the blood at the end of the capillaries?
Capillaries - about 97.5% saturated with O2 (PO2 = 100mmHg)
How saturated is the Hb is systemic arterial blood? How much oxygen does it carry? How much is bound to Hb?
- Systemic arterial blood - 97% saturated
- 19.8mL of O2 per dL: 0.29mL in solution and 19.5mL bound to Hb.
How saturated is the Hb is systemic venous blood? How much oxygen does it carry? How much is bound to Hb?
- Hb is 75% saturated
- Total O2 content is about 15.2 mL/dL: 0.12mL in solution and 15.1mL bound to Hb
At rest, how much oxygen do tissues remove from each litre and in total? From Hb or from solution?
- 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
Three important conditions affect the oxygen-haemoglobin dissociation curve. What are they and how do they affect it?
- 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.
What is the P50 of the oxygen haemoglobin dissociation curve?
- 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.
What is the Bohr effect?
- 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.
What is 2,3-DPG? How is it formed? How does it effect oxygen?
- 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 changes 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.
What increases and decreases the levels of 2,3-DPG?
- 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.
Airflow through the respiratory system can be broken down into three interconnected regions. What are they and what do they consist of?
- 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.
The nose is the primary point for inhaled air. In addition to olfaction, the nose and upper airway provides two additional cruical features in airflow. What are they?
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
What happens to smaller particulates that enter the nasopharynx?
- 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.
The conducting airway is made up of a variety of specialised cells that provid more than simply a conduit for air to reach the lung. What are they?
- 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.
How is the epithelium organised in the conducting airways?
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.
As the conducting airway transitions into terminal and transitional bronchioles, the histological appearance of the conducting tubes change. How?
- 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
Epithelial cells in the conducting airway can secrete a variety of molecules that aid in lung defense. What are they? What do they do?
- 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.
What is the “mucociliary escalator”?
- 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).
How quickly can the ciliary mechanism move particles away from the lungs?
At a rate of at least 16mm/minute
In what situations is ciliary motility defective? What are the consequences of this?
- 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.
The walls of the bronchi and bronchioles are innervated by the autonomic nervous system. What triggers this and what is the effect?
- 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.
What affect do different adrenergic receptors have on the conducting airways?
The β2-adrenergic receptors help mediate bronchodilation. They also increase bronchial secretions (e.g. mucus), while α1-adrenergic receptors inhibit secretions.
What is the total cross-sectional area in the alveoli? How does this effect velocity?
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.
The alveoli are lined by two types of epithelial cells. What are they and what is their morphology?
- 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.
What is the function of type II alveolar cells?
- They are important in alveolar repair as well as other cellular physiology.
- One prime function is the production of surfactant.
How do type II alveolar cells produce surfactant?
- 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.
What is the role of surfactant in the lungs? How is it related to surface tension and how does this happen?
- 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
The alveoli are surrounded by pulmonary capillaries. What separates the air and the blood?
In most area, air and blood are separated only by the alveolar and the capillary endothelium, so they are about 0.5μm apart.
What other specialised cells do the alveoli contain?
- Pulmonary alveolar macrophages (PAMs)
- Lymphocytes
- Plasma cells
- Neuroendocrine cells
- Mast cells
Pulmonary alveolar macrophages (PAMs) are an important component of the pulmonary defense system. Where do they come from? What do they do?
- 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.
What is the purpose of the pleural cavity?
The pleural cavity and its infoldings serve as a lubricating fluid/area that allows for lung movement within the thoracic cavity
How does the intrapleural pressure relate to atmospheric pressure? How does this help with breathing?
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
Is inspiration an active or passive process? How does it happen? What are the pressures?
- 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.
At the end of inspiration, what happens to the lungs and the pressure? Passive or active?
- 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.
Strong inspiratory efforts reduce intrapleural pressure to values as low as what? How does this effect lung inflation and deflation?
-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.
What do modern spirometers directly measure?
Direct measurement of gas intake and output.
What does diagnostic spirometry assess?
A patient’s lung function for purposes of comparison with a normal population, or with previous measures from the same patient.
What is the tidal volume? What is its typical value?
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
What is the inspiratory reserve volume? What is its typical values?
The air inspired with a maximal inspiratory effect in excess of the TV is the inspiratory reserve volume.
Typically around 2L
What is the expiratory reserve volume? Typical values?
The volume expelled by an active expiratory effort after passive expiration is the expiratory reserve volume - around 1L
What is the residual volume? Typical value?
The air left in the lungs after a maximal expiratory effort if the residual volume
Typical value around 1.3L
What is the total lung capacity? Typical value?
The inspiratory reserve volume + tidal volume + expiratory reserve volume + residual volume
Typical value around 5L
What is the vital lung capacity? Typical value?
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
What is the inspiratory capacity? Typical value?
The maximum amount of air inspired from the end-expiratory level (IRV + TV).
Typically around 2.5L
What is the functional residual capacity? Typical value
The volume of air remaining after expiration of a normal breath (RV + ERV)
Typically around 2.5L
What is the forced vital capacity?
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
What is the FEV1?
The forced expiratory volume expired during the first second of forced expiration
How is the FEV1/FVC ratio used clinically?
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.
What is alveolar ventilation and how is it related to anatomical dead space and resp rate?
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
How can you physically measure the anatomic dead space?
- 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.
What are the four phases of the single-breath N2 curves when measuring anatomic dead space? What do the points of the curve mean?
- 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;
What is the Bohr equation? What does it calculate?
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.
PICO2 x Vd is so small that it can often be ignored…. so Vd = Vt - (PECO2 x Vt)/(PaCO2)
What is the pressure of a gas proportional to?
Its temperature and number of moles occupying a certain volume
What do gases diffuse through from the alveoli to the blood in the pulmonary capillaries?
Across the thin alvelocapillary membrane made up of the pulmonary epithelium, the capillary endothelium, and their fused basement membranaes
Whether or not substances passing from the alveoli to the capillary blood reach equilibrium in the 0.75 seconds that blood takes to traverse the pulmonary capillaries at rest depends on what? Give some examples and what type of limits them?
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.
How is the diffusing capacity of the lungs for CO (DLCO) measured? Why?
- 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)
When sampling alveolar air, which portion of air do you collect?
- 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.
What is the alveolar gas equation? What is it used to work out?
- 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
What are the effects of decreased barometric pressure on hypoxaemia? Why? How does it change at different levels?
- 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.
How are the partial pressures of water vapor in the alveolar air and CO2 linked to barometric pressure and altitude?
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.
What happens over time during acclimitisation?
- 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.
How do disease processes that prevent ventilation of some of the alveoli create a ventilation-perfusion mismatch? What is the effect of this?
- 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.
In what situations does anaemia cause hypoxia?
- 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.
Why is carbon monoxide toxic?
- 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.
How is compliance measured? What curve does this create?
- 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.
Describe the pressure-volume curve of the lungs?
- 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 (PW) and a slightly positive pressure from the lungs (PL)
- The pressure in the total respiratory system (PTR) is positive at greater volumes and negative at smaller volumes.
How can you measure compliance from the pressure-volume curve?
- Compliance of the lung and chest wall is measured as the slope of the PTR 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.
What does compliance depend on and how does it vary due to this?
- 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.
What diseases shift the pressure volume curve? How do they effect compliance?
- 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
How can you work out the work of breathing from the pressure volume curve?
- 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.
The magnitude of surfactant at various lung volumes has been measured by distending lungs with saline and air while measuring the intrapulmonary pressure. What do the curves measure? Why?
- 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.
When are the differences between the saline and air curves in the pressure volume curves? What is the term used to describe this?
- 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.
The difference between the saline and air curves is much smaller when lung volumes are small. Why?
The low surface tension when the alveoli are small is due to the presence of surfactant in the fluid lining the alveoli.
Formation of the phospholipid film of surfactant is greatly faciliated by the proteins in surfactant. What are they and what do they do?
- 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.
What is the pressure gradient in the pulmonary system? How does it differ from the systemic circulation?
The pressure gradient in the pulmonary system is about 7 mmHg, compared with a gradient of about 90 mmHg in the systemic circulation
What is the pulmonary capillary pressure and oncotic pressure? What does this make the pressure gradient? How does this differ in disease?
- 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.
Gravity has a relatively marked effect on the pulmonary circulation. How?
- 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.
What is the pressure in the capillaries at lung apex? How does the pressure in the respiratory circulation change affect capillaries? When do they collapse?
- 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.
How do the alveolar and capillary pressure effect blood flow in the middle portions of the lungs? How do pulmonary veins fill? What is the waterfall effect?
- 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.
The compression of vessels produced by alveolar pressure decreases and pulmonary blood flow increases as the arterial pressure increases toward the base of the lung. How is blood flow determined in the lower portions of the lung?
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.
How does the myoglobin dissociation curve differ from the Hb dissociation curve? What does this mean clinically?
- 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.
When is O2 released from myoglobin? How does the curve represent this? How is this functionally relevant?
- 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
What happens to the CO2 that diffuses into red blood cells?
- 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
Some of the CO2 in the red cells reacts with the amino groups of haemoglobin. What do they form? How does O2 binding affect this?
- 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.
What is the Haldane effect?
- 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.
Because the rise in the HCO3- content of red cells is much greater than in plasma as the blood passes through the capillaries, about 70% of the HCO3- formed in the red cells enters the plasma. What happens to the remaining 30%? How does this happen? What is the outcome of this? How quickly does it happen
- 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.
For each CO2 molecule added to a red cell, there is an increase of one osmotically active particle in the cell - either an HCO3- or a Cl-. What are the consequences of this? How are they removed?
- 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.
What are the different fates of CO2 in plasma and in red blood cells?
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
How are plasma proteins effective buffers?
They are effective buffers because both their free carboxyl and their free amino groups dissociate:
How does the haemoglobin buffer system work? How does it compare to the plasma protein system? Why?
- 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.
How does the action of imidazole groups of deoxyhaemoglobin differ to those of oxyhaemoglobin?
- 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.
What is the major buffer system in the blood?
The carbonic acid-bicarbonate system.
What is the clinically relevant form of the Henderson-Hasselbach equation for the carbonic acid-bicarb system?
How is a respiratory acidosis caused?
- 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.
How is a respiratory alkalosis caused?
- 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.
How is a metabolic acidosis caused?
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.
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
How is a metabolic alkalosis caused?
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.
In response to metabolic acidosis and alkalosis, how does the respiratory system compensate?
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
Renal tubule cells in the kidney have active carbonic anhydrase. How does this affect their ability to compensate acidosis and alkalosis?
- 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
Where are the main components of the respiratory control pattern generator responsible for automatic respiration?
- 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.
How do the pacemaker cells in the pre-Bötzinger complex control respiration?
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
Dorsal and ventral groups of respiratory neurons are present in the medulla. Is respiratory activity abolished if they’re cut? Where do they send their neurons to?
- Lesions of these neurons do not abolish respiratory activity
- They apparently project to the pre-Bötzinger complex pacemaker neurons.
How does stretching of the lungs effect the regulation of respiration?
- 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
Each carotid and aortic body (glomus) contains islands of two types of cells surrounded by fenestrated sinusoidal capillaries. What are the cell-types and what do they do?
- 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
Where are the afferent nerve fibres from the chemoreceptors? Where do they go to? What is their diameter and speed?
- 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.
Is there a graded increase in afferent impulses from the chemoreceptors depending on levels of arterial PO2?
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.
How do the type 1 glomus cells in the carotid and aortic bodies send impulses through the afferent nerves?
- 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.
The chemoreceptors that mediate the hyperventilation produced by increases in arterial PCO2 after the carotid and aortic bodies are denervated are located in the medulla oblongata. Where in the medulla are they and what do they do?
- 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.
What is the linear relationship between respiratory minute volume and the alveolar PCO2? Why?
- 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.
The essentially linear relationship between respiratory minute volume and the alveolar PCO2 in this graph naturally has an upper limit. How does your body respond if there is too much CO2? What level is this?
- 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)
What is the ventilatory response to oxygen deficiency? At what level does it happen?
- 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
What are the effects of hypoxia on the CO2 response curve?
- 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.
What are the effects on ventilation with decreasing the alveolar PO2 while holding the alveolar PCO2 constant?
- 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
What are the Hering-Breuer reflexes?
- 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.
Why does periodic breathing happen?
- 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.
Why might blood lactate start to rise during exercise?
- 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
How does ventilation change during exercise?
- 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.
Why does ventilation follow this pattern when starting to exercise?
- 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.
The response to graded exercise is shown in this figure. Talk me through it.
- 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.
What is a nephron? How many does each kidney have?
- 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
What forms the glomerulus?
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)
What makes the glomerular filtrate?
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.
How do the afferent and efferent arterioles in the glomerulus vary in size?
The diameter of the afferent arteriole is larger than the efferent arteriole
Two cellular layers separate the blood from the glomerular filtrate in the Bowman’s capsule. What are these? How do they differ?
- 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.
Stellate cells called mesangial cells are located between the basal lamina and the endothelium in the glomerulus. What is their function and where are they especially common?
- 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
How big is the proximal convoluted tubule? How thick is its wall and what features does the wall have?
- 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.
The convoluted proximal tubule straightens and the next portion of each nephron is the loop of Henle. What is the cellular structure of this?
- 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.
How does the loop of Henle size change throughout the kidney?
- 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
The thick end of the ascending loop of Henle reaches the glomerulus of the nephron from which the tubules arose and nestles between its afferent and efferent arterioles. What are the specialised cells at the end?
- 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.
The distal convoluted tubule starts at the macula densa. How long is it and what is its cellular structure?
- 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
The distal tubules coalesce to form the collecting ducts. How long are these? Where do they go?
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 .
The epithelium of the collecting ducts are made of two types of cells. What are they and what do they do?
- 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.
What is the layout of the renal circulation?
- 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
Does the kidney have a portal system?
- 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
The capillaries draining the tubules of the cortical nephrons form a peritubular network. What do the efferent arterioles from the juxtamedullary glomeruli drain into? What is the structure of this?
- 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
In practice, how we work out renal clearance using inulin?
- 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.
How does the net filtration pressure change throughout the kidneys? Why does this happen? What does this mean?
- The net filtration pressure (PUF) 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
How does tubular function effect substance excretion?
- The amount of any substance (X) that is filtered in the product of the GFR and the plasma level of the substance (ClnPX).
- 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
How do you work out the amount of a substance excreted by the tubules?
- The amount of the substance excreted per unit of time (VXV) equals the amount filtered plus the net amount transferred by the tubules
- This latter quantity is conveniently indicated by the symbol TX
- 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.
How does the structure of the epithelium help with tubular transport?
- 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
The reabsorption of Na+ and Cl- plays a major role in body electrolyte and water homeostasis. Where is sodium transported in the nephron?
- 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.
What are some of the apical transporters and functions of them in the proximal tubule?
Na/glucose co-transporter - uptakes both glucose and Na+
Na+/Pi co-transporter - Na+ and PI 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
What are some of the apical transporters and functions of them in the thick ascending limb of the loop of Henle?
Na/K/2Cl co-transporter - Na+, Cl- and K+ uptake
Na/H exchanger - Na+ uptake, H+ extrusion
K+ channels - K+ extrusion (recycling)
What is the apical transporter and its function in the distal convoluted tubule?
There is a NaCl co-transporter that uptakes both Na+ and Cl-
What is the transporter in the collecting duct and what is its function?
There is an ENaC Na+ channel that uptakes sodium
What are the lateral intercellular spaces in the tubules and what is their role?
- 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
Where is most of the sodium transported in the kidneys?
- 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.
Glucose, amino acids and bicarbonate are reabsorbed along with Na+ in the early portion of the proximal tubule. How is glucose reabsorbed? How quickly is it filtered? How much is reabsorbed?
- 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.
What is the amount of glucose reabsorbed proportional to? What is the transport maximum? What happens above this?
- The amount reabsorbed is proportional to the amount filtered and hence to the plasma glucose level (PG) times the GFR up to the transport maximum (TmG).
- When the TmG is exceeded, the amount of glucose in the urine rises.
- The TmG is about 375mg/min in men and 300mg/min in women
The renal threshold for glucose is the plasma level at which the glucose first appears in the urine in more than normal minute amounts. Where would this be predicted and where is it actually?
- One would predict that the renal threshold would be about 300mg/dL, that is, 375mg/min (TmG) 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 TmG in all the tubules was identical and if all the glucose were removed from each tubular when the amount filtered was below the TmG.
- 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.
What is the mechanism of glucose reabsorption?
- 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.
How does SGLT-2 transporter bind to glucose?
- 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
Like glucose reabsorption, amino acid reabsorption is most marked in the early portion of the proximal convoluted tubule. How does this happen?
- 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.
The dynamics of PAH transport illustrate the operation of the active transport mechanisms that secrete substances into the tubular fluid. How does this change with different plasma levels? How does this differ to glucose?
- The filtered load of PAH is a linear function of the plasma level, but PAH secretion increases as PPAH rises only until a maximal secretion rate (TmPAH) is reached.
- When PPAH is low, CPAH is high; but as PPAH rises above TMPAH, CPAH fall progressively
- It eventually approaches the clearance of inulin (Cin) 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 PG levels below the renal threshold; but above the threshold, CG rises to approach CIn as PG is raised.
What is the sensor for the tubulo-glomerular feedback and how does sense changes? What does it produce
- 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
Once adenosine has been secreted from the basal membrane of the tubular cells. What impact does it have on the renal tubule?
- 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.
How does the macula densa react to an increase in GFR?
- 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
Active transport of many substances occurs from the fluid in the proximal tubule, but studies have shown that the fluid remains essentially iso-osmotic until the end of the proximal tubule. Where is aquaporin-1 and what role does it have in this?
- 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.
How much solute and water gets removed in the proximal tubule? Why?
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
The loops of Henle of the juxtamedullary nephrons dip deeply into the medullary pyramids before draining into the DCTs in the cortex, and all the collecting ducts descend back through the medullary pyramids to drain at the tips of the pyramids into the renal pelvis. How does the osmolality change throughout the loop of Henle?
- 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 Hb</sup>O, 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.
Why does the osmolality change throughout the loop of Henle?
- 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.
In the thick ascending loop, Na+, K+ and 2Cl- are transported from the tubular lumen into the tubular cells. How does this happen?
- 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.
How does the K+ and Cl- diffuse back into the tubular lumen after being transported into the renal tubule cell?
- 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
What happens in the distal tubule?
- 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
The collecting ducts have two portions. What are they?
A cortical portion and a medullary portion
The key to the action of vasopressin on the collecting ducts in aquaporin-2. Where is aquaporin-2 stored? What does it do?
- 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
What is the maximum osmolality of urine?
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
What does the urine concentrating mechanism depend on?
- 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
What are the steps that theoretically take place in the loop of Henle that create a countercurrent mechanism?
- 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
The osmotic gradient in the medullary pyramids would not last long if the Na+ and urea in the interstitial spaces were removed by the circulation. These solutes remain in the pyramids primarily because the vasa recta operate as countercurrent exchangers. How do they do this?
- 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
It is important to recognise the difference between osmotic diuresis and water diuresis. What is this?
- 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
What is the free water clearance?
- In order to quantitate the gain or loss of water by excretion of a concentrated or dilute urine, the “free water clearance” (CH2O) is sometimes calculated.
- This is the difference between the urine volume and the clearance of the osmoles.
Where is K+ reabsorbed and secreted? What is the rate of K+ secretion proportional to? Why?
- 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
How is the reabsorption of Na+ and the secretion of K+ linked?
- 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.
What cells is the bladder epithelium made of and what innervates it?
- 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
The relation between intravesical pressure and volume can be studied by inserting a catheter and emptying the bladder, then recording the pressure while the bladder is filled with 50mL increments of water or air (cystometry). How will it change? What is this graph called?
- 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
The flatness of segment Ib is a manifestation of the law of Laplace. How?
- 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
The bladder smooth muscle has some inherent contractile activity; however, when its nerve supply is intact, how is a reflex contraction triggered?
- 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.
Do the sympathetic nerves to the bladder play any part in micturition? What is their role?
- 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.
What is the body’s response to an increase in the effective osmotic pressure of the plasma?
- Vasopressin secretion is increased and the thirst mechanism is stimulated
- Water is retained in the body, diluting the hypertonic plasma
- Water intake is increased
What is the normal plasma osmolality and maximal inhibition of vasopressin secretion?
- 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
How does vasopressin respond to osmotic stimuli? What is this regulated by?
- 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)
What is the relationship between the rate of vasopressin secretion and the discharges from the stretch receptors? Is it stretch receptors in the low or high pressure portions of the vascular system that have the most effect on vasopressin secretion?
- 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
How does haemorrhage affect vasopressin release and the osmotic response curve?
- 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
What does angiotensin II do?
- 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
The existence of various natriuretic hormones has been postulated for sometime. Two of these are secreted in the heart. Where are they? What triggers their release?
- 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
When is ANP secreted? What is its concentration in humans?
- 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
How does immersion in water up to the neck affect renin and aldosterone?
It decreases the secretion of renin and aldosterone because it counteracts the effect of gravity on the circulation and increases central venous pressure
What does erythropoietin do?
- 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
Where does renal H+ secretion take place?
- 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+
What transporter is involved in H+ secretion in the proximal tubules?
- 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
Once the H +ion has been secreted into the tubule lumen, what happens to it?
- 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
Inside the proximal tubule cell, carbonic anhydrase is also present. What does it do there? What happens with the products of this reaction?
- 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.
How does H+ get secreted from the distal tubules and collecting ducts?
- 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
How does the H+ secretion get increased in acidosis?
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
The I cells in the distal tubules and collecting ducts also contain anion exchanger 1. What and where is this? What does it do?
- 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
What is the limiting pH in the urine for H+ secretion? Where does this occur in the kidney? How can we alter the pH of the urine in the kidney?
- 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); HPO42- to form H2PO4-; and with NH3 to form NH4+.
The three buffers of importance in the renal handling of acid and its secretion into the lumen are bicarbonate, dibasic phosphate and ammonia. What proportion of acid do these three mechanisms get rid of?
- Approximately 40% of non-volatile acids is excreted as titratable acid (i.e. phosphate system)
- 60% of non-volatile acid is excreted as HN4+.
What is the concentration of HCO3+ and phosphate in the plasma and glomerular filtrate? How does this affect H+ binding in the kidney?
- 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<sup-</sup> 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.
How does the tubule cell continue to have high levels of H2CO3-?
- 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
Secreted H+ in the kidney also reacts with dibasic phosphate (HPO42-) to form monobasic phosphate (H2PO42-). Where does this happen and why does it happen there?
- 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
How does the ammonia equilibrium stay in equilibrium?
- 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
How is NH4+ produced in the cells?
- 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-+
How doe the pH change along the nephron?
- 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
How do amino acids produce NH4+ and bicarb? Do these go into the circulation?
- 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
What are the principal buffers in body fluids?
The intestine is composed of functional layers. What are they?
- 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
The epithelium of the intestine is further specialised in a way that maximises the surface area available for nutrient absorption. What is this?
- 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
What is the structure of the salivary glands? How do these features help with its role?
- 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.
What regulates saliva secretion?
- 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
How does the anatomy of the stomach aid its role? Which parts of the stomach secrete which things?
- 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
Where in the stomach glands do the secretions mix with mucus? Where does this open onto?
- 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
How is gastrin triggered? What is the process after it has been released?
- 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.
There are three primary stimuli of gastric secretion, each with a specific role to play in matching the rate of secretion to functional requirements. What are they?
- 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
Gastric parietal cells are highly specialised for their unusual task of secreting concentrated acid. How does it change at rest and when secreting?
- 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.
How does the proton pump in the parietal cells change at rest and then when they begin to secrete?
- 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.
What ion transport takes place on the apical membrane of the parietal cells in the stomach?
- 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.
The portion of the pancreas that secretes pancreatic juice is a compound alveolar gland resembling the salivary gland. How does it secrete the juice?
- 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)
Where does the ampulla of Vater open into? What surrounds the opening?
- 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.
What is the pancreatic response to IV secretin?
As the volume of the pancreatic secretion increases, its Cl- concentrations falls and its bicarb concentration increases.
Although bicarb is secreted in the small ducts of the pancreas, it is reabsorbed in the large ducts in exchange for Cl-. What is this inversely proportional to?
The magnitude of the exchange is inversely proportional to the rate of flow
When considering bile as a digestive secretion, it is the bile acids that represent the most important components. Where are they synthesised and secreted? What are the main five? Which are primary and secondary?
- 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.
Bile acids are amphipathic.What does this mean and how does it affect their structure?
- 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
What happens to bile acids after they are secreted?
- 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
How much fluid is presented in the intestines each day, how much is reabsorbed and how much is lost in the stool?
- 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/
In the period between meals, what absorption is taking place in the small intestine and how does it happen?
- 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.
What absorption takes place in the colon in the period between meals? How can your diet affect this?
- 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
Despite the predominance of absorptive mechanisms, secretion also takes place continuously throughout the small intestine and colon to adjust the local fluidity of the intestinal contents as needed for mixing, diffusion and movement of the meal. How does the secretion take place?
- 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
What cells secrete gastrin? Where are they and what size are they? Where are the receptors for gastrin?
- 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
Where is cholecystokinin secreted? What are its main actions?
- 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
It addition to its primary action of stimulating gastrin secretion, what are cholecystokinins other roles?
- 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
What regulates the secretion and inhibition of cholecystokinin?
- 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.
Where is secretin secreted and what is its structure? What other intestinal hormones is it similar and dissimilar to?
- 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.
What is the role of secretin and how does it do it?
- 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
What regulates the secretion of secretin?
- 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
What is GIP? Where is it produced? What stimulates its secretion?
- 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.
Two major networks of nerve fibers are intrinsic to the GI tract. What are they? What do they constitute?
- 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.
What is special about the gastrointestinal (splanchnic) circulation?
- 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.
The principal dietary carbohydrates are slit into three groups. What are they and what is in each group?
- 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.
How are starches broken down by α-amylase throughout the GI tract? What are the products of this?
- 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.
What does the transport of glucose and galactose depend on? Why?
- 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)
What are the different members of the SGLT family? What do they? How do they resemble the GLUT transporters?
- 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.
How do sodium and glucose get transported into the intestinal cells and into the interstitium and capillaries?
- 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.
Glucose transport is an example of secondary active transport. Why? What is the outcome of this?
- 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.
In the small intestine, the polypeptides formed by protein digestion in the stomach are further digested by the powerful proteolytic enzymes of the pancreas and intestinal mucosa. What are some of these enzymes? How do they work?
- 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.
The endopepidases only break down the interior peptide bonds from the protein digested in the stomach. Where does the final digestion to amino acids occur?
- 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.
How are the dipeptides and tripeptides transported into enterocytes? How are they transported out again?
- 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
Fats are relatively insoluble, which limits their ability to cross the unstirred layer and reach the surface of the mucosal cells. What happens to help them reach the mucosal cells?
- 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
By which mechanism are lipids absorbed?
- 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.
The fate of fatty acids in enterocytes depends on their size. How?
- 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.
How do the larger fatty acids get esterified in the mucosal cells of the intestine?
- 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
What form is most of the iron in the diet and what form is the form that is absorbed? How does this get transformed?
- 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.
Almost all iron absorption occurs in the duodenum. How does it happen?
- 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.
How is iron transported in the plasma?
- 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.
How is heme related to iron absorption?
- 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
70% of the iron in the body is in Hb, 3% is in myoglobin and the rest is in ferritin. where is ferritin? What are ferritin aggregates called?
- 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
The intake of nutrients is under complex control involving signals from both the periphery and the central nervous system. Many of the hormones and other gators that are released coincident with a meal are also involved in the regulation of feeding behaviour. What are some examples of this?
- 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.
The amount of energy liberated per unit time is the metabolic rate. What is the equation for this? What is the peak efficiency for isotonic muscle contractions to perform work?
- 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
With this equation, what makes up the heat?
- 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
What is the respiratory quotient and the respiratory exchange ratio? What is the difference? What is RQ for carbs, protein and fat?
- 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
When the meal is present in the intestinal tract, the enteric nervous system promotes a motility pattern that is related to peristalsis but is designed to retard the movement of the intestinal contents along to length of the intestinal tract to provide time for digestion and absorption. What is this called?How does it happen?
- 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.
Except in the oesophagus and proximal portion of the sotomach, the smooth muscle of the GI tract has spontaneous rhythmic fluctuations in membrane potential. What values does it fluctuate between? What cells cause it and how?
- 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
During fasting between periods of digestion, the pattern of electrical and moor activity in the GI smooth muscle becomes modified. How? What are the phases? How quickly do they move?
- 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.
What triggers the migrating motor complexes in the GI tract? How does the level of this change? What else is secreted with the MMCs?
- 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
What nerves cause swallowing?
- 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.
What is the physical process of swallowing?
- 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.
What is the action of the lower oesophageal sphincter? When is it active?
- 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.
The lower oesophageal sphincter is made up of three components. What are they?
- 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
What is the neural control of the lower oesophageal sphincter?
- 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
Irritation of the mucosa of the upper GI tract is one trigger for vomiting. How does it trigger it? What are some other central causes of vomiting?
- 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
Chemoreceptor cells in the medulla can also initiate vomiting when they are stimulated by certain circulating chemical agents. How?
- 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.
The colon serves as a reservoir for the residues of meals that cannot be digested or absorbed. How does the motility of the colon reflect this? How much fluid is removed?
- 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.
When does the ileocecal valves open and close?
- 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).
The movements of the colon include segmentation contractions and peristaltic waves like those occurring in the small intestine. What is a third type of contraction that occurs only in the colon? How does it happen?
- 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.
At what pressures does the urge to defecate occur and the reflux expulsion of the contents of the rectum occur?
- 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
Before the pressure that relaxes the external anal sphincter is reached, voluntary defecation can be initiated by straining. How does this take place?
- 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
What is the gastrocolic reflex?
- 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
An important function of the liver is to serve as a filter between the blood coming from the GI tract and the blood in the rest of the body. How does it do that?
- 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
How does the structure of each hepatic lobule aid in its role?
- 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.
Where are Kupffer cells in the hepatocytes?
Numerous macrophages (Kupffer cells) are anchored to the endothelium of the sinusoids and project into the lumen
Each liver cell is also opposite to several bile canaliculi. How do these drain?
- 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.
The functional unit of the liver is the acinus. What is the set-up of this and the oxygenation of it?
- 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.
What is the mean pressure or the portal venous pressure, hepatic venous pressure and the hepatic artery?
- 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.
A marked pressure drop occurs along the hepatic arterioles. Why is this pressure drop adjusted? How does it happen?
- 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.
In the period between meals, many of the hepatic sinusoids are collapsed. How does this change following a meal? How does this cause ascites?
- 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
Most of the bilirubin in the body is formed in the tissues by the break down of haemoglobin. How does this happen?
- 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.
Why is the liver critical for ammonia handling in the body? Why is this important?
- 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
What is the life story of ammonia?
- 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
Phosphatidylcholine that enters the bile forms mixed micelles with the bile acids and cholesterol. How can this form gallstones?
- 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
How does the hepatic bile duct compare to the gallbladder bile in regards to percentage of solids, bile acid concentration and pH?
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
I normal individuals, bile flows into the gallbladder when the sphincter of Oddi is closed (the period in between meals). How does the absorption of water change? What does this to do the concentration of solids?
- 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.
What is the anatomy of the thyroid?
- 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.
What is the anatomy of the thyroid parenchyma? What does each part do? How does it change when the gland is active and inactive?
- 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”
What is the cellular microanatomy of the thyroid gland?
- 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
What are the hormones secreted by the thyroid?
- 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
Dietary iodide is absorbed by the intestine and enters the circulation. How much is needed and what happens to it then?
- 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.
How is iodide transported into the thyrocytes?
- 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.
How does iodide exit the thyrocytes?
- 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.
How is iodide used to form thyroid hormones and what molecule is used to do it?
- 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.
Colloid represents a reservoir of thyroid hormones, and
humans can ingest a diet completely devoid of iodide for up to 2 months before a decline in circulating thyroid hormone levels is seen. What happens when the hormone is required?
- 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.
Thyrocytes thus have four functions. What are they?
- 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.
How much of each thyroid hormone is made per day?
- 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.
What is the difference between free T3/T4 and total T3/T4? What is the function of the protein binding?
- 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.
What are the plasma proteins that bind to thyroid hormones?
- 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.
How much T4 is normally protein bound? What is its half-life?
- 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.
How much T3 is normally protein bound? What is its half-life?
- 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.
Where are thyroid hormones metabolised? Why?
- 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
Three different deiodinases act on thyroid hormones. What are they? Where are they? and what do they do?
- 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.
Thyroid function is regulated primarily by variations in the circulating level of pituitary TSH. How?
- 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.
Is T3 or T4 more potent? Why?
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.
The adrenal medulla, which constitutes 28% of the mass of the adrenal gland, is made up of interlacing cords of densely innervated granule-containing cells that abut on venous sinuses. Two cell types can be distinguished morphologically. What are they and which one is there more of?
- 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.
What is the action of ACTH?
- 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.
The calcium in bone is of two types. What are they and how are they regulated?
- 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 Ca2+, 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 Ca2+ interchange between plasma and this stable pool of bone calcium is only about 7.5 mmol/d.
How is calcium absorbed?
- 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+
How is calcium excreted?
- Plasma Ca2+ is filtered in the kidneys, but 98–99% of the filtered Ca2+ 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.
How is phosphate controlled by the kidney?
- PI in the plasma is filtered in the glomeruli, and 85–90% of the filtered PI is reabsorbed.
- Active transport in the proximal tubule accounts for most of the reabsorption and involves two related sodium-dependent PI 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
The active transport of Ca2+ and PO4
3- from the intestine is increased by a metabolite of vitamin D. How does the body receive vitamin D?
- 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.
How is vitamin D metabolised?
- 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.
How does vitamin D exert its effect on calcium?
- 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
The formation of 25-hydroxycholecalciferol does not appear to be stringently regulated. However, the formation of 1,25-dihydroxycholecalciferol in the kidneys, which is catalyzed by the renal 1α-hydroxylase, is regulated in a feedback manner by plasma Ca2+ and PO43+. How does this happen?
- 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 PO43– levels and inhibited by high plasma PO4
3– levels, by a direct inhibitory effect of PO43– 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.
What are the different cell types in the parathyroid gland? What do they do?
- 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.
What are the actions of PTH?
- 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<sup2+</sup> 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.
The cells in the islets can be divided into types on the
basis of their staining properties and morphology. Humans have at least four distinct cell types: A, B, D, and F cells. What do they secrete? Where are they within the pancreas?
- 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.
Where is insulin secreted?
- 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.
How is insulin produced?
- 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.
What are the rapid, intermediate and delayed actions of insulin?
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
What are the actions of insulin in different tissues?
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
GLUT-4 is very insulin sensitive. How is it affected by it?
- 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.
How does glucose intake trigger an initial spike of insulin secretion?
- 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.
How does glucose cause a more long-lasting increase in insulin?
- 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.
What is the action of glucagon and how does it do it? (on a cellular level)
- 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.
Glucagon does not cause glycogenolysis in muscle. How does it increase glucose levels?
- 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.
