Physiology Flashcards
cells do not live in isolation they use signalling for
they receive and act on signals from beyond their plasma membrane
-growth
-differntiation and development
-metabolism
when signalling goes wrong
-cancer
-diabetes (islets of langaarhans)
do bacteria signal
-bacteria have membrane proteins that act as information receptors
receptors movement to or from stimulus or formation of spores
plant cells respond to
-variations in sunlight
-growth hormones
-gravity
animals cells respond to
-metabolic activities of neighbouring cells
-place cells during embryogenesis by recognising developmental signals
-exchange info about ion and glucose concentrations
unicellular eukaryotes respond to
-local environment
-mating signals
principles of signalling
1)signal
2)receptor
3)amplification
4)response
ligands that stimulate pathways are called
agonists they are signals
different types of signal
-direct contact = protein(ligand) binds to receptor
-gap junction = exchange small signalling molecules and ions
-autocrine = ligand induces a response only in signalling cycle for example hela cells cam grow on their own due to this EICOSANOIDS = autocrine ligands
-paracrine = the ligand induces a response in target cells close to the signalling cells
endocrine signalling
ligand is produced by endocrine cells and is carried in the blood inducing a response in distant target cells the ligands are often called hormones
paracrine example
acetylecholine as its released into a neuromuscular junction
specificity is provided by two mechanisms
-certain receptors are only on certain cells
-molecules downstream of the receptor only present in some cells
developmental controls
specify which genes are expressed in which cell type genes can be turned on or off by interaction of positive/agitators and negative repressor/regulators with enhancer or silencer control elements
specificity is linked to affinity
-molecular complementarity between ligand and receptor
association rate definition and formula
since there are two reactants the reaction is second order and the rate at which it occurs is determined by concentrations of both reactants and by a constant K+
association rate = K+[R][L]
R = receptor and L = ligand
K+ units
M^-1s^-1 per molar per second
dissociation rate
determined by first order and the rate at which it occurs is determined by concentrations of this reactant and by constant K
Dissociation rate = K_[RL]
K_ units
S^-1
K+ ad K_ are equal therefore
Keq = [Rl]/[E][L] M^-1 this gives the affinity
he dissociation equilibrium equation
Kd = k_/k+ or flip and get k+/k_ (M)
key principle of binding
it is dynamic a mixture of association and dissociation
signalling are amplified
by enzyme cascades which can amplify several orders of magnitude within MILISECONDS
signalling :desensitisation
-when a signal is present continuously the signal transduction pathway becomes desensitised and when it falls below a threshold the system regains sensitivity
signalling :cross-talk
-most signalling pathways share common components leading to potential cross talk
signalling :integration
-if multiple signals are given the cell produces a unified response( a combo of both)
some receptors are enzymes for example
insulin receptor (IR)
insulin
lowers blood sugar levels
what do epinephrine and cortisol do
epinephrine: raises blood sugar levels
cortisol : raises
islets of langerhaans what each one does
alpha:glucagon
beta:insulin
delta:somatostatin
the insulin receptor
Following translation, the receptor subunits:
1 enter the ER (endoplasmic reticulum) membrane,
2 associate into dimers,
3 and are exported to the cell surface, via the Golgi complex.
4 During intracellular transport, the proteins are processed by cleavage, each into an α and a β subunit.
5 At the plasma membrane, they are displayed as trans-membrane proteins
insulin signalling starts at the plasma membrane …
stimulates an allosteric change in IR bringing the cytosolic domains close allowing activation
insulin signalling first step
-activated IR phosphorylates and activates the insulin receptor substrate
insulin signalling adaptor proteins Grb2 and Sos
Activated IRS-1 is bound by the adaptor molecules Grb2 and Sos.
Insulin signalling: recruitment of Ras
Sos converts inactive (GDP-bound) Ras to active (GTP-bound) Ras.
Insulin signalling; signal transduction and amplification
Activated Ras recruits Raf kinase to the membrane and activates its protein kinase activity. RAF phosphorylates and activates MEK kinase. MEK phosphorylates and activates mitogen- activated protein kinase (MAPK).
The adaptors Grb2 and Sos are common to both EGF and insulin signalling, so activation of EGFR and IR recruits the same MAPK cascade … which means the same genes are modulated in the downstream response.
insulin receptors and glucose regulation
IRS-1 is bi-functional.
It also recruits and activates phosphoinositide 3-kinase (PI-3K) to the cytosolic face of the plasma membrane
PIP3 is a second messenger.
First messenger/primary messenger/ligand:
an extracellular substance (for examples, the hormone epinephrine or the neurotransmitter serotonin) that binds to a cell-surface receptor and initiates signal transduction that results in a change in intracellular activity
second messenger:
a small metabolically unique molecule, not a protein, whose concentrations can change rapidly. Second messengers relay signals from receptors to target molecules in the cytoplasm or nucleus.
glucose regulation and PIP
-PIP3 recruits PDK1 (PIP3-dependent protein kinase).
-PDK1 activates protein kinase B (PKB). NB! Care…PKB is also called Akt. The terminology can be confusing.
How/why does IR signal through two pathways?
Why?
A rationale: there’s not much point in growing if there is no food supply.
Do all cells respond to both pathways?
No: terminally-differentiated cells do not respond to the growth signal because of loss of signalling chain components.
Which cells regard insulin as a growth factor? Fibroblasts are the best example.
cellular responses to insulin WITHIN HOURS
- increased expression of liver enzymes that synthesise glycogen
- increased expression of adipocyte enzymes that synthesise triacylglycerols
- increased expression of genes involved in mitogenesis in some cell lines
Termination of the fast Ras-independent pathway
A PIP3-specific phosphatase (PTEN) removes the phosphate at the 3 position of PIP3 to convert it into PIP2. PDKI and PKB can no longer be recruited to the plasma membrane, shutting off signalling through PKB.
Lim et al 2011 type II diabetes
-normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol.
-Patients increased their exercise levels and ate a VERY restricted diet of ~600 kcal (600 Cal) per day for 2 months
-25% of patients were unable to maintain this lifestyle change
Of the remaining 75% …
… in all cases, weight loss was accompanied by
a possible rewiring of the brain (?) – salads looked like food a reduction in diabetic symptoms
a restoration of insulin sensitivity
BMI 1835 Adolphe quetelet
weight/(height x height)
>30 obese
< 25 normal
the lipostat theory 1953
-postualtes that eating behaviour is inhibited when body weight exceeds a certain value
-postulates that energy consumption increases above set point THEREFORE restriction of eating and more exercise should reduce body mass BUT the opposite happens feedback stimulates eating behaviour when adipose tissue is lost
evidece for lipostat
-soluble factor called leptin is released into bloodstream by adipose
-leptin binds to receptors in hypothalamus
ENDOCRINE due to action at DISTANCE
leptin discovery
identified in mice product of Lep^OB gene (obese)
the number and she of adipocytes is increased in Lep^ob/lep^ob mice
the leptin receptor is the product of
the Lepr^DB gene expressed in hypothalamus
what does leptin do
-released by adipose tissues
-releases Alpha-Melanocyte stimulating hormone that modulates nervous transmission
effects,
-suppressed appetite
-sympathetic nervous system
-increased BP/HR and thermogeneisis
janus kinase(JAK)
cytosolic non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway
have two almost identical phosphate transferring domains
erythropoietin (EPO)
hormone cytokine that controls the development of erythrocytes RBCs from precursor cells in the bone marrow
used for aneamia in RARE cases
G-protein coupled receptor (GPCR) structure
-7 transmembrane domains snake through membrane
GPCR ligand binding
-fold into tertiary structure barrel which forms cavity in membrane
-cavity is ligand-binding domain for small ligands
ligand binding CHANGES THE RELATIVE OIENTATIONS OF the TM helices (twisting motion)
GPCR conformational change
-ligand binding alters the conformation of the TM domains and reveals amino acids in teh cytosolic domains for activating heterotrimeric G-proteins
GPCR bound to heterotrimeric G protein
-as it is a trimer of alpha, beta and gamma subunits that is inactive when bound to GDP but active when bound to GTP
-ligand binding alters receptor shape which induces nucleotide exchange the replacement of GDP of the G alpha with GTP
GPCR dissociation
-following G alpha activation the G-protein dissociates from the receptor to yield a G alpha-GTP monomer and a tightly interacting G beta gamma dimer
-these now modulate the activity of other intracellular proteins
GPCR regulation
-G alpha has slow GTP hydrolysis activity this regenerates the inactive form of the alpha subunit allowing reassociation with G beta gamma dimer to form the resting G-protein which can again bind to GPCR and await activation
Flight or fight? Hormones
cortisol
-increases blood sugar through gluconeogensis
-suppresses immune system
epinephrine
-adrenergic receptors (GPCRs)
cAMP is a second messenger
-epinephrine binds beta adrenergic GPCR receptor, G alphas is activated and stimulates adenylate cyclase
-result is increase in cAMP levels in the cell
effects of cAMP
-protein kinase A (PKA) which affects transcription factors, ion channels and a variety of other enzymes
pathways with cAMP are usually given same response
therefore epinephrine and glucagon both raise blood glucose levels and induce triglyceride breakdown
light reception
-in the vertebrate eye, light passes through the neural layer
-through the cell bodies of the light receptor cells (rods and cones) and acts as a signal in the discs of photoreceptive membrane in the outer segment of the retina
light receptors
-inner and outer segments of a photoreceptor cell is a primary cilium(act as signals)
rod cells discs
-the outer segment contains 1000 discs not connected to plasma membrane
-each is a closed sac of membrane with embedded photosensitive rhodopsin molecules
rhodopsin STRUCTURE
a visual pigment specialised GPCR made of
-opsin (GPCR component) linked to 11-cis-retinal a prosthetic chromophore
retinal and light capture cis-trans isomerisation
1)alternating single and double bonds form polyene with a long unsaturated network of electrons that can absorb light energy
2)light absorption causes cis-trans isomerisation around the C12 and C13 bond
3)the N of the key lysine moves 0.5 nm
LIGHT ENERGY IS CONVERTED INTO ATOMIC MOTION WITHIN A FEW PICOSECONDS
light capture: activation of the GPCR
-light absorption by retinal alters the conformation of GPCR (inactive rhodopsin becomes activated metarhodopsin II WHICH stimulates nucleotide exchange on teh alpha subunit of a specific heterotrimeric G protein called transducin (Gt)
the cGMP-gated ion channels close
-hyperpolrising the membrane . a light stimulus has been converted to a change in the electrical charge (potential) across a membrane
rhodopsin sensitivity and insensitivity
peak absorbance 500 nm
rod cell can respond to a single photon
about 5 such responses lead the brain to register a flash of light
light closes the cGMP gated ion channels reducing influx of Ca++
-Ca++ is extruded by Na+/Ca++ anti porters therefore Ca++ concentrations in the cell fall if low enough granulate cyclase is activated causing cGMP to rise again
light activated rhodopsin can be phosphorylated by
rhodopsin kinase
-therefore more light = more phosphorylation
rhodopsin: very light insensitivity (SUMMER NOON)
-arrestin binds to fully phosphorylated rhodopsin and this stops activation of transducin
-Rhodopsin kinase and arresting also inhibit other GPCRs not just rhodopsin
3 mechanisms that make rods insensitive to light
-prolonged cGMP gated channel closure
-phosphorylation of opsin reduces transducin activation
-arrestin binding to phosphorylated opsin stops transducin activation
trichromatic
3 visual pigments
human colour vision relies on three visual pigments
-412-426 nm
-530-532 nm
-560-563 nm
monochromatic vision
-an opsin (modified GPCR) with
-11 cis-retinal as the chromophore and there is a different transducin
colour tuning
-amino acid differences in the trans-membrane segments of the protein component alter the electronic environment that surrounds the 11-cis-retinal chromophore
what di birds see peacocks
-7 year Japanese study concluded that female choice was not influenced by peacock tails birds have a WIDER spectrum than us therefore we cannot make assumptions based off of our eye sight
cephalopod (octopus eye) vs human eye
cephalopod
-light strikes retina directly vs indirectly
-no blind spot
-retina only has rod cells
John dalton 1766-1844 hypothesis
colour blind and postulated that the vitreous humour in his eyes was tinged blue that absorbed red light and that people with clear vision must have clear humous in eyes
clout blindness genetic mutational causes
-whole colour spectrum is altered
selective pressure for human trichromacy
-did human vision coevolve with production of colours in maturing fruit
1777: report of people with defective vision very poor at slecting ripe fruit
so shouldn’t dichromate have a selective disadvantage or does it help them spot other things
summer 1940 US camouflage planes
-one colourblind observer spotted all 40 planes compared to observer who spotted 10
sildenafil citrate
-second most successful drug of all time
-similar structure to cGMP therefore it is a inhibitor of cGMP phosphodiesterase SIDE EFFECT blue tinged vision
nitric oxide and signalling
1847
-nitroglycerine (NG) was discovered by Ascanio sobrero in Turin. He noted the violent headache produced by minuet quantities of NG on tongue
-NG was used as a headache cure a homeopathic use
-1867 brunt used AMYL NITRATE to relieve angina
-1876 Murrell tried NG for angina and used a more stable version
how does nitric oxide signal? it activates guanlyate cyclase
-soluble gas that can diffuse across membrane
-binds to guanalyte cyclase synthesises cGMP teh second messenger altering the activity of target proteins
1)the gas NO
2)Diffusion
3)activates its receptor
4)activated receptor (GC) converts GTP into cGMP
5)cGMP is a second messenger that alters the activity of target proteins
nitric oxide is written as NO* because
it has a free radical (unpaired electron)
Angina treatment today
-glycerol trinitrate remains the treatment of choice
-other organic esters and inorganic nitrates are also used
NO* production in vivo is stimulated by high BP
1)autonomous nerves in the vessel wall respond to high BP and release acetylcholine (Ach)
2)acetylcholine binds its receptors (AchR) on the membrane of endothelial cells
NO* production in vivo is stimulated by high blood pressure
Increased [Ca++] and nitric oxide synthase
-Ca++ is a second messenger
-high Ca++ activates nitric oxide synthase (NOS)
-NOS catalyses the conversion of arginine to citrulline and nitric oxide
NO* now acts as a paracrine signal to smooth muscle
NO* is unstable.
It is converted to nitrate and nitrite within 10 seconds.
This short life means it can communicate only over short distances (paracrine signalling, neighbouring cells).
NO* activates soluble guanylate cyclase by binding to its haem group, causing a conformational change.
GC converts GTP to cGMP
cGMP is a second messenger
cGMP activates protein kinase G in smooth muscle
PKG is a cGMP-dependent protein kinase.
It phosphorylates myosin light chain.
Muscle cells with phosphorylated myosin light chain relax.
Smooth muscle relaxation causes dilation of the blood vessel.
Dilation increases the volume of the vessel and lowers blood pressure.
other sources of NO* and its effect
-an amyl nitrate inhalation spray is commonly prescribed for a weak heart
-it vaporises to generate NO* which dilates vascular model
Cyclic nucleotides and PDE5
-cyclic nucleotides are important secondary messengers that control many physiologic processes including smooth muscle contractillity
-phosphodiesterases (PDEs) a superfamily of that cleave 3’,5’-cyclic phosphate
sildenafil citrate/ viagra is
cGMP mimic
-potent inhibitor of cGMP phosphodiesterases
-most active against phosphodiesterase 5
oestrogen and the oestrogen receptors (ERs)
-4 types on poster
-steroid hormones synthesised from androgens(male sex hormones)
-oestrogen receptors written as estrogen
the ER is cytosolic
-the ER has an N-terminal transactivation domain, a DNA binding domain, and a hormone binding domain that can bind oestrogens
-it is stored in the cytosol in complex with a dimeric chaperone protein called Hsp90
-it binds near the ligand-binding site and maintains the ER in a soluble state (COMPLEX TOO LARGE TO ENTER THE NUCLEUS)
Steroid hormone signalling is unusual: no amplification
The ER is the receptor for oestrogen.
Oestrogen-activated ER binds DNA and directs transcription of oestrogen-response genes.
This means that ONE protein is both receptor and effector. There are no amplification steps via protein cascades or via second messengers.
Steroid hormone signalling is unusual: no amplification
The same is true of other steroid hormone receptors – and the receptors for thyroxine and retinoic acid.
there are multiple isoforms of the ER
-two different forms alpha and beta each encoded by a separate gene
-plus splicing variants large combinational repitoire
what does the nervous system do?
1)receive and interpret information about the internal and external environments of the body
2)make decisions about the information integrating system
3)to organise and carry out action motor system
neuron doctrine (circa 1894) With Golgi body stain
The neuron is the structural and functional unit of the nervous system
Neurons are individual cells, which are not continuous to other neurons
The neuron has three parts: dendrites, soma (cell body) and axon
Conduction takes place in the direction from dendrites to soma, to the end
arborisations of the axon
how should we classify neurones?
-morphology
-internuerones
-neurotransmitter
Anterograde transport
WGA-HRP)
From soma, down axon to terminals
Two kinds: rapid: 300-400 mm/day
(up to 1 μm/s)
slow: 5-10 mm/day
Retrograde transport
(HRP)
From terminals to soma
Worn out mitochondria, SER
Rapid: 150 - 200 mm/day
encephalisation quotient
=brain weight/ body weight
expected linear relationship with sharks through frogs but but gyri makes brain smaller
brain structures defined by embryology
4 weeks
Prosencephalon
Forebrain
Mesencephalon
Midbrain
Rhombencephalon
Hindbrain
6 weeks
Prosencephalon:
Diencephalon
Telencephalon
the meninges
-surround the CNS
-brain surrounded by cerebrospinal fluid
3 layers
1)tough outer layer
2)arachnoid mater
3)pia mater
the ventricular system
Principle source of CSF: choroid plexuses in ventricles
About 150 ml CSF
25 ml in ventricles
125 ml in subarachnoid
spaces in brain & sp cord
Renewed ~ 4-5 times in 24 hrs
Removes waste products
Supplies brain & sp cord with nutrients
Buffers changes in blood pressure and protects brain
Supplies brain with fluid during dehydration
Allows the brain to remain buoyant
The motor-sensory homunculus redrawn
Homunculus derived from the vertical length measurements. (D) Homunculus derived from the number of stimulation points
intracellular glass microelectrodes
-cells are very small so hard to get inside
-first glass micro electrodes LING and GERARD 1949
making the membrane potential more negative is
hyperpolarising
making the membrane potential more positive is
depolarising
resting membrane potential requires
JULIUS BERNSTEIN 1880s
-intact cell membrane
-ionic concentration gradients and ionic permeabilities
-over the long term metabolic processes
at equilibrium there is a balance between
K+ ions moving in and out of the cell which occurs at the resting potential
how membrane potential changes with extracellular [K+] if membrane is only permeable to K+ ions
-reduces electrical gradient to balance
-as we increase K+ concentration outside cell membrane potential becomes depolarised
rising phase of action potential due to Na+ influx
-found action potential needs Na as less Na lower action potential make
Na+ channels allow influx of Na+
Voltage-gated channels: transmembrane proteins
Activated by changes in voltage (depolarisation)
Selective for ionic species eg Na+, K+, Ca2+ etc
What initially depolarises neurones to open
the voltage-gated Na+ channels?
Synaptic transmission: excitatory postsynaptic potentials EPSPs
Generator (receptor) potentials (sensory neurones)
Intrinsic properties (eg pacemaker activity in heart)
Experimental (eg electrical stimulation)
Ion flow during the action potential
Around threshold Vm, the membrane becomes much more permeable to Na+ ions
This leads to depolarisation and further recruitment of VG Na+ channels
Depolarisation results in VG Na+ channels inactivation (closure)
After a delay VG K+ channels open
Both contribute to the repolarisation of the membrane after the action potential
two things contribute to repolarisation
1)Na+ channels close
2)voltage-gated K+ Chanels open
concentration gradient outward: 125 mM inside 5 mM K+ outside
electrical gradient outward: positive
THEREFORE K+ MOVES OUT OF NEURON
voltage gated Na+ channel inactivation
ball and chain model
1)positively charged activation gate keeps channel closed
2)depolarisation of membrane causes activation gate to swing out of the way allowing Na+ ions to enter and cause further depolarisation
3)the inactivation “ball” rapidly enters the channel to block Na+ influx
refractory periods absolute vs relative
-The absolute refractory period (ARP) starts from when VG Na+ channels open and continues for ~1 ms.
-During this time it is not possible to elicit another action potential
-The ARP is due to VG Na+ channel inactivation.
-The relative refractory period (RRP) continues for 2–3 ms after the ARP
-Action potentials can be elicited, but requires stronger or longer stimulation.
-The increased K+ permeability during the RRP makes it harder to depolarise the membrane to activate VG Na+ channels and elicit an action potential.
action potentials are initiated at the axon
hillock
bigger axon diameter =
faster conduction
Myelination greatly accelerates action potential velocity
saltatory conduction
synaptic cleft is
20-40 nm wide
sicles are
40-50 nm
axodendritic synapses
synapses that one neuron makes onto the dendrite of another neuron.
how is neurotransmitter packaged in vesicles
A non-peptide neurotransmitter is
synthesized in the nerve terminal
and transported into a vesicle
-proton gradient drives vesicle filling
neurotransmitter release
4 basic steps
1. Docking/priming
2. Ca2+ entry
3. Vesicle fusion (exocytosis)
4. Recycling of vesicles (endocytosis
neurotransmitter release 1)docking of vesicles to membrane
1)docking of vesicles to membrane
-combo of SNAP and SNARE proteins anchor vesicles to the presynaptic membrane
-docked vesicles are ready to release their contents
neurotransmitter release 2) Ca 2+ entry into nerve terminals
The action potential:
1) depolarises nerve terminal via voltage-gated Na+ channels
2) opens voltage-gated Ca2+ channels
3) Ca2+ moves into the nerve terminal down its electrochemical gradient into the neuron
neurotransmitter release 3)Ca2+ entry leads to fusion of docked vesicles
and release of neurotransmitter (exocytosis)
Ca2+ binds to one of the SNARE proteins (synaptotagmin, is the Ca2+ sensor )
Important features of Ca2+-dependent neurotransmitter release
Neurotransmitter release requires binding of multiple Ca2+ ions (between 3 to 5).
Neurotransmitter release occurs very quickly after Ca2+ entry
Blocking Ca2+ entry blocks synaptic transmission (cadmium and toxins from spiders/snails)
Knockout of synaptotagmins: lose fast synchronous neurotransmitter release
neurotransmitter release 4) endocytosis (vesicle recycling
Blocking endocytosis (eg with Dynasore, which inhibits dynamin) leads to rapid synaptic depression
Identifying a substance as a neurotransmitter
- Must be synthesised in the neuron
- Show activity-dependent release from terminals
- Duplicate effects of stimulation when applied exogenously
- Actions blocked by competitive antagonists in a concentration-dependent manner
- Be removed from the synaptic cleft by specific mechanisms
somatic nervous system
voluntary movement
in humans there are __ pairs of spinal nerves
31
white matter:
-axonal tracts
-ascending and descending
-motor and sensory
dorsal grips carry info to
the dorsal part (back) of spinal cord
ventral spinal cord
ventral (which means “towards the stomach”)
nerves are multiple
nuerons and can be bungled together in fasicles
upper and lower motorneurones
UMN are in spinal cord and LMN in muscle
gyrus
part of Brain that sticks up
sulcus
dips down
corticospinal pathway
is the major neuronal pathway providing voluntary motor function. This tract connects the cortex to the spinal cord to enable movement of the distal extremities
motor units
neuromuscular junctions or motor end-plates
muscle fibres and single motor neuron
motor units
different sizes
-when a motor neuron is activated all the muscle fibres that it innervates contract
-motor units are intermingled throughout muscles
-dine control = small motor units
-coarse control = large motor units (2000 muscle fibres)
motor units contain Differnt types of skeletal muscle type 1:
Slow oxidative (ATP oxidative phosphorylation)
Speed of contraction: slow
Force generated: low
Small motor units
skeletal muscle type 2
Fast oxidative (ATP oxidative phosphorylation)
Speed of contraction: intermediate
Force generated: intermediate
Intermediate motor units
Fast glycolytic (ATP through glycolysis)
Speed of contraction: fast
Force generated: high
Large motor units
neurotransmitter and nicotinic
Acetylcholine activates
nicotinic receptors on muscle
Nicotinic receptors are
ion channels (inotropic)
Permeable to Na+, K+ and Ca2+
Depolarise muscle fibres
single contraction of muscle is
twitch
increasing force of contraction through a few steps
1) recruitment = smaller motor units recruited first(lower threshold)
2)temporal summation = twitches dont have time to decay therefore they get bigger
unfused vs fused tetanus
unfused has small time to relax
some muscles show fatigue
less muscle tension each time
Why do muscles show fatigue?
-Protective/ defence mechanism
Causes
Depletion of glycogen
Accumulation of extracellular K+
Accumulation of lactate
Accumulation of ADP + Pi
Central fatigue
tendon organs in muscle
detect how much the muscle has contracted and tells brain
muscle spindles
tell brain how much muscles have stretched
-intra/extrafusal
Golgi tendon reflex
-Monitors tension in the muscle
-Protects muscle to prevent damage
-Tendon reflex less sensitive than stretch reflex
but can override it
sensory system
Right side to LH
sensory dermatomes
each spinal nerve innovates a part of skin (called the dermatome)
adaptation sensory tonic
Slowly adapting
Mechanoreceptor
Eg Merkels disks
Would constantly feel stimulus
adaption sensory neurones phasic
-rapidly adapting
mechanoreceptor
pacinian corpuscle
only feel stimulus at beginning (clothes on body dont feel constantly)
receptive fields
area where sensory neurone can pick up that it was activated
enables two point discrimination
flexion reflex
withdraw leg
functions of the autonomic nervous system
Contraction/ relaxation of smooth muscle
Exocrine and endocrine secretion
Control of the heartbeat
Steps in intermediary metabolism
autonomic ganglia vs sensory
-preganglionic fibres these neutrons have dendrites those in sensory are unipolar
two branches of ANS
Sympathetic
preganglionic transmitter: acetylcholine
postganglionic transmitter: noradrenaline
Except: Adrenal glands /sweat glands
Parasympathetic
Preganglionic transmitter: acetylcholine
Postganglionic transmitter: acetylcholine
sympathetic innervation of adrenal gland
-80% adrenaline, 20% noradrenaline
two branches of ANS have different functions
Parasympathetic
Rest and digest (satiation and repose)
Sympathetic nervous system
Fight or flight (stress, exercise response)
In some situations symp and para have opposing actions
but not in all.
Both exert physiological control over the body under normal
circumstances when the body is at neither extreme.
paravertebral chain (sympathetic chain)
are located just ventral and lateral to the spinal cord. The chain extends from the upper neck down to the coccyx, forming the unpaired coccygeal ganglion.
autonomic tone
Most tissues receive a basal level of autonomic activity
Examples
Blood vessel = sympathetic tone = Partial constriction
Heart = vagal tone = decrease during exercise
eye is controlled by parasympathetic or sympathetic?
both
ciliary muscle when relaxed
far vision
Micturition
Reflex
bladder-to-bladder contraction reflex for which the reflex center is located in the rostral pontine tegmentum (pontine micturition center: PMC). There are two afferent pathways from the bladder to the brain. One is the dorsal system and the other is the spinothalamic tract.
horner syndrome
combination of symptoms that arises when a group of nerves known as the sympathetic trunk is damaged. The signs and symptoms occur on the same side (ipsilateral) as it is a lesion of the sympathetic trunk. It is characterized by miosis (a constricted pupil), partial ptosis (a weak, droopy eyelid), apparent anhidrosis (decreased sweating), with apparent enophthalmos (inset eyeb
all muscle
Transduce chemical and electrical commands to produce a
mechanical response (motor output)
Two types of muscular contraction:
isometric
isotonic
isometric contrcation
-no change in length
-increase in tension (pushing against something)
isotonic
tension remains unchanged
shortening of length when overcome load
-(lifting object)
structure of cardiac muscle
-myocytes
-linked via intercalated disks
-electrically coupled via GAP JUNCTIONS
-similar to skeletal muscles
properties of cardiac muscle cells
Differences between atria, conducting system and ventricles
Striated like skeletal muscle
Shows myogenic activity
Cells are electrically coupled
T system (ventricular muscle)
Controlled by autonomic nervous system and hormones
properties of smooth muscle
Muscle of internal organs (blood vessels, gut,
glands etc)
Heterogeneous
Can maintain a steady level of tension (tone)
Produce slow long lasting contractions
Spindle-shaped cells linked together by
mechanical and electrical junctions
No cross striations but does contain actin
and myosin: loose lattice
Innervated by the ANS (varicosities)
Very plastic properties: can adjust length over
a much wider range than skeletal or cardiac muscle
sphincters
rings of muscle constricted most of time
basically the butthole
skeletal muscle appearance
striated appearance because of sarcomeres (a band etc…)
siding filament mechanism
myosin pulls actin together
The force produced by muscle contraction depends on:
1.Number of active muscle fibres (recruitment)
2.Frequency of stimulation (temporal summation, tetanus vs twitch)
3. Rate at which muscle shortens
4. Cross sectional area of the muscle
5. Initial resting length of the muscle
t system and sarcoplasmic reticulum
sarcolemma = plasma membrane
sarcoplasmic reticulum = which releases calcium
t system = action potential travels down t system
muscle contraction requires ATP
-phosphocreatine lasts for 10s about 15-50 mM present in muscle
-glycogen stored in muscle
slow-twitch fibres (type 1)
Metabolism: oxidative phosphorylation
Number of mitochondria: High
Glycogen storage: high
Contraction rate: slow (~15 mm per second)
Relaxation rate: slow
Can maintain tension for prolonged periods
Resistant to fatigue
Example: muscles that maintain body posture such as
soleus muscle of lower leg
Fast-twitch fibres
Contraction rate: high (40-45 mm per second)
Type IIa (fast oxidative fibres)
Metabolism: oxidative phosphorylation
Number of Mitochondria: very high
Glycogen storage: high
Fatigue resistant
Type IIb (large diameter, white muscle)
Metabolism: glycolytic (anaerobic)
Number of mitochondria: fewer (limited blood supply)
Glycogen storage: high
Rapid fatigue
Required for short periods i.e. sprinting
Most muscles are mixtures of different fibre types
caclium ions are required for muscle contraction
-initiation of cross-bridge cycling in skeletal and cardiac muscle
calcium reveals myosin binding sites
how does muscle intracellular (Ca2+) increase
Opening of voltage gated Ca2+ channels
following depolarisation (SK, SM, C)
Opening of intracellular Ca2+ release channels on SR
(SK, SM, C)
Ca2+ entry from SR (action of hormones etc)
(SM)
skeletal muscle is depolarised by
acetylcholine at neuromuscular junction
How is muscle depolarisation (excitation) coupled to contraction?
action potential travels through t system
Contraction is terminated by calcium calcium removal
1.Small amount of Ca2+
is extruded from the cell
- Most taken up into the SR
by a SERCA-type pump requires ATP
Excitation-contraction coupling is different in smooth muscle
No T-system
Contraction regulated by myosin
Contraction slower and longer lasting than skeletal muscle
Contraction terminated by Ca2+ removal and dephosphorylation (release of Ca from stores)
CALCIUM ACTIVATES MYOSIN LIGHT CHAIN KINASE(MLCK)
Each side of the human heart pumps 5 litres.min-1
- delivers ~250ml O2.min-1
- removes ~200ml CO2.min-1
AND DELIVERS HORMONES
The human heart works tirelessly
FACTS
Weighs between 200 to 425g.
It is slightly larger than the size of your fist.
It beats ~100,000/day, pumping ~7,000 litres of blood/day.
Over 80 yrs of life, will beat 3 billion times
Humans have the highest number of
lifetime beats
The heart sits centrally with the
apex situated on the
left side (fifth intercostal space)
semi lunar valves are between
ventricles and aorta/pulmonary artery
Chordae
Tendoneae
heart strings
the heart spends twice as much time in diastole as systole
systole:
-Ventricular contraction
~70ml of blood from each ventricle
Lasts around 300 ms
diastole: Relaxation permits filling of the heart
Lasts about 550 ms at 70 beats.min-1
Filling occurs principally during the first 100 – 200 ms
mean arterial pressure
1/3 systole + 2/3 diastole
Starlings law of the heart depends on stretching of cardiac muscles
-output of two pumps in series must be equal
-stroke volume is governed by filling and stretching of muscle
RULE = Energy of contraction is a function of the length of the (cardiac) muscle fibres
-Due to an increased sensitivity
of the contractile proteins to Ca2+
Starling’s law of the heart depends
on stretching of cardiac muscles
increased blood volume = increased stretch of myocardium increased force to pump blood out
conduction pathway of the heart from atria to ventricles
-Heartbeat is myogenic – initiated within the heart itself
-sinoatrial node (SA) – pacemaker of the heart: specialised muscle cells.
-Travels through the atrial muscle to the atrioventricular (AV) node
-Travels to ventricles through Purkinje fibres of the bundles of His and their branches
-It then spreads throughout the myocardium
ionic pacemaker potential depends on calcium not sodium
resting potential is determined by K+
-depolarisation is generated by reduced K+ and increased Na+ permeability
-depolarisation may also be produced by increased calcium permeability because its a POSITIVE ION
Long refractory period prevents
tetanus in cardiac muscle
myocytes are branched muscle cells with a single nucleus
-cylindrical cells often branched with a single central nucleus
-around 50-100 micrometers in length ;5-20 micrometers in diameter
-straited under microscope
myocytes are electrically coupled through intercalated disks
Connected by tight junctions, coupled through connexins
Contraction activated by entry of Ca2+
-Principally from intracellular stores
-Extracellular fluid,
-action potential propagates through the electrical connections
current flow creates
ECG
The circulatory system requires different vessels to accommodate different pressures
-low venous pressure = veins
-higharterial pressure = elastic arteries and muscular arteries
if arteries were completly rigid
-ventricular pressure rises to a max during systole then falls to low
-As blood is pumped into the aorta and major arteries,
they stretch
Thus in systole, more blood flows in than out
the Windkessel effect.
The walls of the aorta and elastic arteries recoil in diastole, maintaining blood flow.
elastic arteries convert intermitten pressure into pulsatile flow
-Aortic pressure rises to a maximum during systole – the systolic pressure
It falls to a minimum during diastole – the diastolic pressure
Flow follows the pressure, but never reaches zero
- It is pulsatile rather than
intermittent.
Blood flow depends on blood vessel radius
Resistance will be determined by 3 factors
Length of blood vessels
Longer blood vessels would provide greater resistance
The length of each vessel remains constant
Viscosity of blood
Blood with a lot of solute would provide more resistance
Solutes such as hemocrit, albumin, etc do not change much under normal circumstances
Radius of blood vessels
ohms law
Q = (P1 – P2)/R,
where Q=flow, (P1-P2) = pressure difference between the two ends and R is the resistance of the vessel
flow becomes turbulent if velocity is high
-The layers (laminae) of laminar flow break up and flow becomes disordered
-In these circumstances, the resistance to flow is raised
Turbulent flow tends to lead to endothelial damage and hence to arterial disease
sphincters control access to the microcirculation
-constrict/dilate arterioles larger therefore less R so path of least resistance can FUNNEL TRAFFIC
permeability is determined in part by the nature of the molecule itself
Lipid soluble molecules = which include O2 and CO2, diffuse easily through capillary cell membranes.
Hydrophilic molecules= travel through pores, via a paracellular route.
Molecules >60kd =are not transferred and many plasma proteins are retained in the circulation – important in the equilibrium between plasma and the e.c.f.
equlibrium is capillary beds are determined by pressures known as starlings forces
Capillary beds as the site at which the equilibrium between plasma and interstitial fluid is established
Governed by ‘Starling forces’
Loss of fluid from the plasma, owing to hydrostatic pressure
Reabsorption of fluid into plasma, owing to colloid osmotic pressure or oncotic pressure
balance is not perfect but its necessary for lymphatic sampling
Any excess of fluid is taken up into lymphatics and returned to the circulation
Larger lymphatics have valves and contract rhythmically
Samples the blood for foreign particles
muscle pump
enhances venous return
-squeezes blood to heart as you stand all blood vessels contract
orthostatic intolerance
postural hypotension
inotropic =
create a greater force of contraction so heart can get much larger and then come back to same place if sympathetic is turned on
blood vessels are only innervated by the
sympathetic
pacemakers and atrial muscle and heart are innervated by
para and sympathetic nerves
both arms of the autotrophic nervous system produce chronotropic effects on the heart
-Sympathetic drives the heart through noradrenaline: Increased rate: a positive chronotropic effect
Increased conduction:
-parasympathetic slows the heart through acetylcholine
decreased rate and decreased conduction
Only the sympathetic nervous system
alters contractility of the heart
-Autonomic nervous system influences contractility
-Sympathetic increases contractility through NA enhancing Ca2+ release in myocytes
a positive inotropic effect
sympathetic nerves release noradrenaline onto smooth muscle
-sympathetic nerve in tunica media cause contraction
NA from varicosities in sympathetic nerve endings
sympathetic nerves stoically release noradrenaline onto smooth muscle
1)control resistance of systemic circulation
2)regulate flow to organs or tissues
Noradrenaline works through myosin
light chain kinase and phosphatase
NA acts on a1 and a2 receptors to mobilise Ca2+ in smooth muscle
Angiotensin II does two things
that affect the circulation
Rapid:
Powerful vasoconstrictor – increase peripheral resistance
– increase venous tone
Slow:
Secretion of aldosterone increases:
– Retention of Na+ (cation of ECF)
– Thirst
– ECF and plasma volume
– Filling pressure
Atrial stretch receptors help
regulate extracellular fluid volume
-Atria have an endocrine function
– secreting atrial natriuretic peptide/factor (ANP).
-Release of ANP
– renal excretion of Na+, and reduction of ECF
volume
Sends information to hypothalamus to decrease secretion of anti-diuretic hormone (ADH)
– Reduce extracellular fluid volume
– Removes vasoconstrictor effect
Potassium and Adenosine act as paracrine signals to counter increased vasomotor tone
-Metabolites oppose sympathetic innervation
-Vasoconstrictor sympathetic nerve fibres
-Are opposed by paracrine effects of metabolites -Metabolites washed away by blood flow
Metabolites ensure local control
exceeds global drives to blood flow
-Vasodilator metabolites ensure flow meets metabolic requirements
Controls blood flow of microcirculation
-Other factors:
- Myogenic contraction of vascular smooth muscle
- Factors released from endothelial cells e.g. NO
- Circulating factors, e.g., angiotensin II
blood must be directed to where it is needed most in brain
Overall flow remains constant
- Alters local flow so supply meets demand
Loss of consciousness (fainting or syncope) occurs if blood pressure drops sufficiently
pulmonary circulation is under low resistance
Pulmonary circuit has high compliance
No change in resistance
respiratory pump
large changes in blood pressure
Allows lung to be more compliant
pulmonary circuit has low resistance
-short distance
-larger diameter
haemorrhage rapid loss of blood
1.. Respond to reduction in blood volume
2. Maintains blood pressure and cardiac output
3. Restore circulating fluid volume
During haemorrhage inital corrections
come from baroreceptor reflexes
Increasing cardiac output
-Elevating heart rate (sympathetic & parasympathetic)
-Enhancing contractility (sympathetic)
Increased drive to vasculature (sympathetic)
-Raising TPR (arterioles constrict in skin, GI, and skeletal muscle)
-Raising venomotor tone (veins constrict)
Secretion of erythropoietin corrects for loss of red blood cells
Reabsorption of interstitial fluid partially restores blood volume
Expense of haematocrit and plasma proteins (colloid osmotic pressure will fall)
Other longer term physiological mechanisms will restore extracellular fluid volume
Secretion of aldosterone, anti-diuretic hormone,
Atrial natriuretic peptide.
Secretion of erythropoietin will restore red cell count
Need to intervene to support
physiological mechanisms
Clinically
1. Treat the cause of blood loss - prevent further bleeding
2. Give fluids – preferably blood, but otherwise saline with
colloid to maintain oncotic pressure
3. Monitor oxygen saturation (oximetry)
4. In severe situations, monitor the filling pressure of the
heart (left atrial pressure) with catheter
increases in filling pressure during exercise would lead to overstretching cardiac muscle
-if filling large became very large
cardiac output fails
-At high filling pressures, stroke volume no longer increases with increasing filling pressure
-Very high filling pressures also lead to oedema –
in the lung if left atrial pressure is high
Reduction in diastole during exercise
protects the heart from overfilling
Cardiac output rises – usually up to 3x (but can rise 5x)
- Increase in CO cannot be sustained through an
increase in SV alone
- Increase in heart rate (from 60 to 180 beats per min)
Increase in heart rate reduces filling time
- Reduced diastole (systole does not change)
- Relatively little increase (10 – 20%) in stroke volume
Protects from overfilling/stretching
Cutaneous vasodilation contributes to thermoregulation during exercise
Need to get rid of excess heat during exercise
Sweating
Cutaneous vasodilation
Cutaneous vasodilation: sympathetic vasodilation system
Problem
Cutaneous vasodilation reduces peripheral resistance and will
divert blood from muscles
- Initially thermoregulation wins out
- If central venous pressure falls sufficiently than
thermoregulation is abandoned.
Hot climates: Heat stroke
coronary circulation
Only 1/10 of mm of endocardial surface can obtain nutrients from blood in chambers
Main arteries on surface, smaller arteries penetrate into the muscle
ventilation and breathing are different aspects of external respiration
External Respiration: Exchange of oxygen and carbon dioxide between an organism and external environment
Breathing: The act of muscle contraction/relaxation to move air in and out of the lung
Ventilation: Movement air from outside to inside the body for exchange of gas between air in thelungsand blood in capillaries within the alveoli
respiratory centres control breathing and send message to respiratory muscles
lea dinging to lung inflation
-gas exchange in arteries
there are 3 aspects to central control of breathing
-voluntart/behavioural
-reflex/automatic
-emotional
reflex/automatic inspiratory rhythm is generated by the prebotzinger complex
-recorded with electrodes the rhymth on nerves
-isolated specific areas to find the breathing area and found the area controlling = inspiratory oscillator
to find what controls expiration
generated by parafacial respiratory group
-found by inducing area found RTN and pFRG control
reflex/automatic control of breathing is coordinated in the ventral respiratory column
pFRG generates expiratory rhythm
-prebotxia complex generates inhibitory
voluntary control of breathing originates in the
motor cortex
-when breathing quickly trunk arms and shoulders lit up because moving upper chest SHOULD BREATHE WITH ABDOMEN
motor cortex neurone that modulate breathing synapse in the pons
-prebotzinger complex is responsible
voluntary control of breathing is remarkable
-human respiratory system is under remarkable voluntary control
-static apnea world records (not swimming) normal or fill body with oxygen
voluntary control cannot be maintained when stimuli such as
Pco2 or H+ become too intense = the breaking point
emotional control of breathing arises through
corticospinal projections dont go through pons (part of 10% that dont)
-thats why upset people can’t talk because emotional control takes over
hypercapnia is a potent regulator of breathing
-even small increases in inhaled CO2 will stimulate breathing
-10% rise in CO2 gives rise to a 100% increase in breathing
-a 20% more than trebles
Hypoxia modulates breathing to a lesser degree than hypercapnia
-Arterial PO2 has to fall to about half normal before breathing is stimulated:
-35% drop in O2 gives rise to a 20% increase in breathing
A 55% drop in O2 is required for breathing to double
peripheral chemoreceptor detect alterations in blood gases - predominantly oxygen
-Carotid bodies, situated close to bifurcation of common carotid arteries in the neck
Aortic bodies, situated
close to aortic arch
Respond to changes arterial blood:
Decreased PO2 (hypoxia)
Increased PCO2 (hypercapnia)
Increased [H+] (acidosis)
80% of O2 detection, and 20% of CO2 detection
Central Chemoreceptors detect alterations in blood gases – predominantly carbon dioxide
Mainly located in medulla oblongata
Can be in other brain structures
Respond to changes in cerebrospinal fluid
Stimulated by increased PCO2 or associated changes in [H+]/pH
70% of CO2 detection, and 30% of O2 detection
Blood gas regulation involves many medullary nuclei
-raphe complex CO2 after P12
-glia sense O2 and Co2
copy detect CO2 in adult
-nucleus tractus solitarius
chemoreceptors summary
central = CO2 excess hypercapnia
peripheral O2 lack (hypoxia)
pulmonary stretch receptors prone ct the lungs
In smooth muscles of bronchi and trachea.
Stimulated by stretch of
-Signal lung volume to brain
Inhibit inspiration and lengthen expiration
Hering-Breuer inflation reflex
Regulating respiratory rhythm e.g. exercise and sleep in neonates.
Rapidly adapting pulmonary stretch receptors monitor irritants
In epithelial cells in larnyx,
trachea and airways.
Respond to mechanical
stress: large inflation/deflation
Respond to chemical environment of lung: noxious gases, dust, cold, histamine.
Constrict airway & promote rapid shallow breathing
Responsible for the “gasping inspirations of the newborn”
Promote cough in trachea and larynx.
Promote sighing due to gradual collapse of lungs (atelectasis): ~5 minutes.
the circuit control for sighing is located in the RTN and pre both
-sigh is two combined breaths one after the other
-Change in lung volume produced by changes in transpulmonary pressure (Ptp)
Compliance: ability to expand lungs at any given change in (Ptp)
There are two major determinants of lung compliance:
1. “Stretchability” of tissues
2. Surface tension within alveoli
Surface tension within alveoli is lowered by pulmonary surfactant
The surface of alveoli is moist
Surface tension at air-water interface resists stretching
Pulmonary surfactant lowers surface tension and increases compliance
compliance:
ability to expand lungs at any given change in (Ptp)
breathing depends on cyclical excitation of respiratory muscles and is comprised of three phases
inspiration
post inspiration
expiration
inspiration
Active: Initiated by activation of the nerves to the inspiratory muscles
post-inspiration
Active: Recruitment of post-inspiratory muscles
slows recoil
expiration
Passive: Inspiratory muscles relax and lungs recoil.
Active: activation of expiratory muscles
external intercostals
-open ribs up and out
diaphragm
main contributor to inspiration
-a muscle
-Asymmetrically innervated (right hand side is greater innervation)
-70% of your Tidal volume
-phrenic nerve
cruel diaphragm
involved in post inspiration
when contracts stop diaphragm from going back into place (MAKING IT SLOWER)
larynx
prevents things occurring while breathing in
liver is stuck to diaphragm why?
transverse abdominis involved in expiration
where we get a stitch
contraction of tongue
supports the airway and reduces resistance during inspiration
prevents collapse of vocal cords
contraction of tongue during expiration
shapes mouth and move air effciently
thorax is a compartment containing three types of plural membrane
-the thorax is a closed compartment
-separated from the abdomen by the diaphragm
-contained by spinal column sternum, ribs and intercostal muscles.
-the lungs and walls of the thorax are covered by tiny membranes - the pleurae
thorax is a compartment containing three types of plural membrane
-the thorax is a closed compartment
-separated from the abdomen by the diaphragm
-contained by spinal column sternum, ribs and intercostal muscles.
-the lungs and walls of the thorax are covered by tiny membranes
costal parietal pleura
covers intercostals
diaphragmatic parietal pleura
cover diaphrgam
mediastianla parietal pleura
cover heart
pleura sides
one connected to muscke
other conncented to lungs
with a gap thsi is so a fluid can be added as a lubricant and acts as a vacuum
the pleurae are kept together by a fluid filled vacuum FOUR KEY TERMS
Visceral pleura: A thin layer of epithelium covering each lung
Parietal pleura: Lines inner surface of the walls of the thorax
Pleural cavity: maintains a partial vacuum which helps keep the lungs expanded
Intrapleural fluid: Allows pleurae to slide over one another
why are pleurae important
differential set points of muscle and lungs generate pressure inside the Plura
-lung always want to expand outwards but teh vacuum fluid stops them
one side pulls in and the other out therefore creates tension
Transpulmonary Pressure is 4 mm Hg
-The transpulmonary pressure (Ptp): difference in pressure between the inside and outside of the lungs within the thorax
-The pressure outside the lungs in the thorax is the intrapleural pressure (Pip)
The pressure inside the lungs is the air pressure inside the alveoli pressure (Palv).
Pneumothorax (collapsed Lung) is causes by air in the plural cavity
A pneumothorax is a collection of air in the pleural space
It occurs when perforation of the lung or chest wall allows air to enter the intrapleural space
Transpulmonary pressure decreases
Elastic recoil collapses the lung
Mediastinal shift
shift of mediastinum organs
(heart, great vessels, trachea and oesophagus)
to one side of chest cavity
alveolar pressure is responsible for generating air movement in the lung
when Palv is positive air flows in!!!!!!!!!
Boyles law
The absolute pressure exerted by a given mass of an ideal gas is inversely proportional to the volume it occupies if the temperature and amount of gas remain unchanged within a closed system.[1][2]
Inspiratory muscle contractions alters trans- pulmonary pressure to draw air into the lung
Muscles of chest wall and diaphragm contract
Ribs are pulled upwards and the diaphragm flattens
Since Ptp = Palv – Pip
As thorax enlarges, Pip lowers
Transpulmonary pressure increases
Lungs expand
Since Ptp = Palv < Patm
Air moves into lung
Exchange of gases in alveoli and tissues are dependent on the partial pressures O2 and CO2
Net movement of O2 and CO2 between alveoli and blood and between blood and cells is by diffusion
Net diffusion of a gas will occur from a region where its partial pressure is high to a region where it is low
Total pressure is the sum of the partial pressures of all the gases
The partial pressure of a gas is directly proportional to its concentration
The total pressure of a mixture of gases is the sum of the individual pressures (“partial pressures”, e.g. PO2)
Patm = PN2 + PO2+ PCO2 + PH2O = 760 mm Hg
Daltons law
In a mixture of gases, the pressure exerted by each gas (the partial pressure) is the pressure that the gas would exert if it were the only gas in the volume occupied by the mixture.
atmospheric pressure is determined by 2 major gases
-atmospheric air is a mixture of gases
-its due to the sum of teh partial pressures of each components
Patm = PN2 + PO2+ PCO2
P atm = 760 mm Hg
Airway pressure is determined by 3 major gases and water pressure
Lung pressure (760 mm Hg) is equal to atmospheric pressure. Air in the lungs is moist, with H2O exerting a pressure of 47 mm Hg
The remaining pressure is occupied by air in the same proportions as in the atmosphere
Patm - PH2O = PN2 + PO2+ PCO2
760 – 47 = 79% N2 + 21% O2 + 0.03% CO2
In atmospheric air:
PN2 is 79.0% of 713 mm Hg = 563 mm Hg
PO2 is 21% of 713 mm Hg = 150 mm Hg
PCO2 is 0.03% of 713 mm Hg = 0.2 mm Hg
partial pressure of gases in tissue is determined by combustion of glucose
Consumes 70-100% of the oxygen in tissues
Tissue PO2 = 30 mm Hg
Produces 45-70 mm Hg PCO2
Tissue PCO2 = 45 mm Hg
Dead Space elevates CO2 levels within the body
Anatomical dead space: Volume of gas within the conducting airways
Increases PCO2 in the alveoli
Physiological dead space: Volume of gas not involved in gas exchange
The two are almost equal in healthy lungs
Exchange of gases in alveoli and tissues are dependent on the partial pressures O2 and CO2
Net diffusion of a gas will occur from a region where its partial pressure is high to a region where it is low.
O2 diffuses from the alveoli into the lung capillaries since:
Alveolar PO2 > Pulmonary PO2
CO2 diffuses from the lung capillaries into the lung since:
Alveolar PCO2 < Pulmonary PCO2
Carbon Monoxide Poisoning occurs because CO2 dissolved in plasma does not change
The ODC for haemoglobin in the presence of carbon monoxide is left-shifted and reduced in size, if drawn with oxygen content of haemoglobin on the y-axis.
The respiratory tree =
comprises the branching structures from the trachea to the alveoli
The respiratory system can be divided by anatomy and also by function
The respiratory system comprises:
The upper airways
The lower airways
The conducting zone
The respiratory zone
The upper airways run from the
mouth and nostrils to the larynx
Also known as the upper respiratory tract
The mouth, nose, pharynx and larynx comprise the upper airways
Infection symptoms include: cough, sneezing, nasal discharge, runny nose, nasal congestion, fever, sore throat.
Obstruction of the upper airways causes snoring during sleep
The lower airways run from
the larynx to the alveoli
A.K.A. the lower respiratory tract
The lower airway extends from the top of the trachea to the alveoli
Infection symptoms include: Bronchitis, oedema shortness of breath, weakness, fever, coughing and fatigue
Affect gas exhange
The conducting zone
runs from the mouth and nostrils to terminal bronchi
Air exchange does not occur
in the conducting zone
Upper airways and part of lower airways
Conducting zone extends from mouth and nose to terminal bronchioles
Conducts air but does not exchange gas
The conducting zone moistens
the air and protects the lungs
Provides a low-resistance pathway for airflow
Does NOT contribute to gas exchange in the lung
Warms (or cools) and moistens the air
Defends against microbes, toxic chemicals and other foreign matter
Continual upwards beating of cilia is an essential mechanism in lung protection
Hair-like projections from epithelial cells that line the airways
Constantly beat upward toward the pharynx
Are immobilized by many noxious agents
Mucus works in conjunction with cilia to provide a escalator
to remove toxins
Mucus is moved from the lung to the stomach where toxins can be neutralised
Mucus is secreted by glands and epithelial cells lining the airways
100 mL/day
Particulate matter and bacteria in inspired air sticks to the mucus
Continuously moved by cilia to the pharynx
Swallowed
Every 30 seconds
Macrophages in alveoli provide a last line of defence for the lung
Phagocytic cells that are present in the airways and the alveoli
Engulf and destroy inhaled particles and bacteria
Injured by noxious agents, e.g. air pollutants and cigarette smoke
Increased airway resistance in asthma is due to
muscle constriction and mucus production
Bronchitis is a conducting zone disorder
Persistent inflammation of the bronchial walls
The airways are inflamed and thickened
Increase in mucus-secreting cells and loss of ciliated cells
Excessive mucus is produced
Obstruction of the airways results, hindering both breathing and oxygenation of the blood
The respiratory zone is the site of gas exchange
The respiratory system comprises three zones:
The upper airways
The lower airways
The conducting zone
The respiratory zone
The respiratory zone is more than just an area of gas exchange
Provides oxygen
Eliminates carbon dioxide
Regulates the blood’s pH in coordination with the kidneys
Influences arterial concentrations of chemical messengers
e.g. conversion of angiotensin I to the potent vasoconstrictor angiotensin II
Traps and dissolves blood clots arising from systemic veins
Pulmonary circulation
Includes blood pumped from the right ventricle through the lungs to the left atrium
Large network of capillaries in the alveolar walls
Low-pressure (15 mmHg)
70 ml of blood
High-flow (5 L blood/min) system
Entire circulating volume
Blood cells spend 0.75s in lung
Alveoli are covered in capillaries to allow for significant gas exchange
Inhaled air is brought into close proximity to “pulmonary” blood
This allows efficient gas exchange between air and blood
Gas exchange in alveoli is optimized by:
Thinness of barrier between blood and the air within the alveolus.
The vast surface area of alveoli in contact with capillaries.
about 1000 capillaries per alveolus
“almost a continuous sheet of blood”
JB West
50 - 100 m2 available for gas exchange
The moist surface of the alveolar cells.
Gas exchange in alveoli is determined by Fick’s law
Fick’s law
Rate of Diffusion ∝ Surface area x difference in concentration
Mismatching of ventilation-perfusion occurs
Ventilation: Amount of gas getting to the lungs
Perfusion: Amount of blood getting to the lungs
Altered by hypoxia sensing cells that constrict vessels to stop blood supplying areas with poor gas exchange
Ideally exactly matched
Regions of low ventilation should have low blood flows (apex of lung)
Regions of high ventilation should have high blood flows (base of lung)
Not gravity, astronauts still show this in space
Closer to diaphragm more effect
The pressures within the lung act to reduce ventilation-perfusion mismatching
Hydrostatic pressure of the liquid increases with depth
Blood pressures increase down the lung’s vertical axis 20 mm Hg
Emphysema is a disorder of the respiratory zone
Lungs undergo self-destruction by proteolytic enzymes secreted by leukocytes
Adjacent alveoli fuse to form fewer but larger alveoli.
Reduces surface area available for gas exchange
Destruction of alveolar walls and collapse of lower airways
Increased airway resistance due to inflammation greatly increases the work of breathing.
COPD rates are rising
In 2011, COPD was the 4th leading worldwide cause of death (after ischemic heart disease, stroke and lower respiratory tract infection).
Predicted to become 3rd leading global cause of death by 2030
Most recent estimates indicate ~65 million sufferers worldwide and ~3 million deaths per annum – 5% of all global deaths
light is focused onto
retina
image are inverted and smaller than reality
brain is great at deterring teh retinal image
structure of retina
photoreceptor layer
then cell body layer
the photopigment - rhodopsin
10^8 pigment molecules/rod
7 transmembrane segments
348 amino acids
Homologous to GPCRs
The light sensitive step
retinal is in teh 11 cis form so when light hits a photon it becomes all trans retinal = change in shape (isomerisation)
The isomerization of retinal changes the conformation of the opsin
(c.f. ligand binding to GPCR) which leads to activation of transducin -a specialized G-protein.
All-trans retinal dissociates from the protein and is recycled via the retinal pigment epithelium
The outer segments of photoreceptors are in close association with the pigment epithelium
the phototransduction cascade
light hits rhodopsin which activates transducin
tehn the transducin binds to cGMP phosphodiesterase (works like GMP) then the cGMP can bind to Na channel leading to influx of Na
e cGMP comes from
GTP binding to guanalyate cyclase becoming cGMP
photoreceptors are depolarised in the dark
hyperpolarisation occurs when light is added when in the dark therefore an action poential cannot be stimulated until its more positive
calcium inhibits
cGMP therefore there is an equlibrium
cyclic nucleotide gated channels
four in odorant receptors and neutrons
Receptive field
A term originally coined by Charles Sherringtonto describe the area of skin from which a scratch reflex could be elicited in a dog.
This concept can be generalised:
If many sensory receptor cells converge and formsynapseswith a singleneuron, they collectively form the receptive field of that cell
only ganglion cells
fire action poetntials
The image on retina
The retina acts as a contrast detector: it detects variations in light across a visual scene, rather than the absolute level of light
On-centre ganglion cells signal rapid increases in light intensity
Off-centre ganglion cells signal rapid decreases in light intensity
Visual information from retina is projected to the brain in an ordered fashion
(visuotopic)
left hemiretinas to left side of brain
Receptive fields of simple cells in visual cortex
1)Specific retinal position
2)Discrete excitatory and inhibitory regions
3)Specific axis of orientation
4)All axes of orientation are represented for each part of the retina
broca on
left therefore can’t speak with right hemisphere
M VS p channel
M channel -analysis of movement
P channel -analysis of fine detail and colour
neurones arranged into
columns
light sensitive ganglion cells (ipRGC)
few direct respond to light
Melanopsin –
an ancient opsin in the ipRGC
Roles of ipRGCs
-low acuity images
-pupillary dialation
-circadian clock entrainment
ear canal transmits
sound to cochelar
We experience sound as a roughly equal increment per 10-fold increase in intensity
Magnitude of sound is expressed on a logarithmic scale:
dB SPL = 20 x log10(P/Pref)
dB SPL, decibels sound pressure level
Where P is the sound pressure and Pref for the threshold of human hearing at 4kHz
Loudest tolerable sound is 120dB SPL (106 fold over threshold)
Basilar membrane is the mechanical analyzer of sound
-the three compartments are filled with fluid
-basillar membrane is the analyser if sound because it virbrates up and down
The Basilar membrane varies along its length
-33 mm long
-At apex it is ~10 times wider than at the base
-Membrane is thin and floppy at apex, thicker and taught at base
sound transducing of cochlear
-30,000 hair cells in teh two cochlea
-inner and outer hair cells have steroecillia
vibrations of the basilar membrane
move the sterocillia
Frequency tuning of IHCs reinforces the tonotopic map of the basilar membrane
hair cells are extremely sensitive to frequencies of sound
hair in location A sensitive to frequency of 11 EXAMPLE
-Successive IHCs differ by about 0.2% in characteristic frequency
The sensitivity of the cochlea is too great and the frequency selectivity too sharp
to result solely from the passive mechanical properties of the cochlea
There must be a means of amplifying sound, especially at low sound intensities
THEREFORE OTOCOUSTICAL EMISSIONS = SOUNDS PRODUCED BY TEH EAR
Prestin
teh motor protein in the plasma membrane
Demonstrating the role of prestin in electromotility and hearing
foudn a mutation that removes prestins ability
-Fragment of prestin showing V499G mutation that removes voltage sensitive conformational change (removes electromotility from single hair cells)
-increases threshold for hearing across the frequency range
steroecillia tip links are
crucial
because leads to mechanosensitive ion channels opening
-once teh ion channel opens there is an entry of K and Ca
-generate potentials In hair cells
influx of k in ion channel and why?
-scala media fluid filled compartment extracts ions from blood (high K concentration)
Advantages of K+
Influx of K+ ions into the sensory cells causes the least change in the cytosolic concentration compared to any other ion. This is because K+ is by far the most abundant ion in the cytosol.
Influx and extrusion of K+ are energetically inexpensive for the sensory cell since both occur down an electrochemical gradient.
Remember the hair cells still have a negative resting membrane potential because their
-basolateral membrane is not in the high K+ endolymph.
-Efflux of K+ through the basolateral membrane generates a resting membrane potential in the normal way
Genetics of hearing loss
1:800 children born with serious hearing impairment
> 60% of people older than 70 suffer sufficient hearing loss to benefit from a hearing aid
> 50 chromosomal loci associated with non-syndromic hearing loss
> 14 genes identified
Some of the molecules in hair cells associated with deafness
-genes asocciated with eharing less are associated with hair cells
-plasma mmbrane pump
GJB2 (Cx26) [postassium cycling]mutations –more than just K+ recycling
Cx26 deletion in mice reduces the endocochlear potential by about 50%
Development of the cochlea itself can be affected if Cx26 deleted early (P1)
but not if deleted later (P10)
Cx26 deletion can cause:
Hair cell degeneration (hair cells themselves do not express connexins). This degeneration can take time to occur.
Affects the electromotility of the outer hair cells (OHCs do not express connexins)
The OHCs still show electromotility but the active cochlear amplification is reduced
A diversion: hair cells in the vestibular system
found in canals*
-so deficits can appear here
Spiral ganglion neurons are the afferent neurons contacting hair cells
Each SGC innervates only one IHC
~10 fibres per IHC, independent coding of each IHC by several SGCs
Tonotopic organization of SGCs
cochlear implant
electrode to try and stimulate and replace the job of the hair cells
tonotopic map in nucleus
-high frequencies go to certain points in cochlear nucleus
neurons in cochlear nucleus
-auditory nerve fibre activate different types of cell based on frequency
and different responses for different cells
medial superior olive
Sound from a source nearest to one ear reaches that ear quicker than the other ear giving rise to inter-aural delays -maximum is 700 s
Minimum discrimination by humans ~10 s
MSO gets inputs from both ears
Projection of inputs from the cochlear nucleus to the MSO and wiring within the MSO gives rise to a place code
ONLY FIRES WHEN SOUNDS ARE SIMULTANEOUS BECAUSE TEH CONDUCTION PATHWAY CAN BE LONGER ON ONE SIDE THEREFOE SIMULATENOUS SOUND IS POSSIBLE
wernickes area
language comprehension
ca
language productiob
Hypoxia
cabin depressurisation effects on human physiology
why does hypoxia occur
the concentration of O2 is constant at 21% at altitudes up to 100,000 feet
-Daltons law:The pressure of a mixture of gases equals the sum of pressures that each gas would exert if it occupied alone the space filled by the mixture
However, atmospheric pressure reduces with altitude
at sea level atmospheric pressure is 1013 mbar
Thus partial pressure of O2 is 212 mbar
At 40,000 feet the partial pressure of O2 is only 39 mbar
The human body has hardly any O2 storage
Onset of hypoxia is associated with mildly euphoric state, rapid loss of critical judgement, slowed thinking and muscular weakness
Victims unaware that they are about to pass out
living at high altitudes
Most locations as high altitude where humans live are near the equator, and have a higher barometric pressure than would be expected
The extra solar radiation causes an upwelling of atmosphere at the equator hence the column of air is higher
Without this Everest could not be climbed without O2
the third man factor by John geiger
-felt they had a companion on their travels up to mount Everest because it occurs during extreme stress
Maximal O2 consumption falls as inspired PO2 is lowered
At 3000 m it is 85%, at 5000 m only about 60%, and on top of Everest only 20% compared to sea level
Consequences are reduced physical power and greatly increased fatigue
Reduced maximal O2 consumption attributed to fall in mitochondrial PO2, but there may be central inhibition from brain
hypoxia symptoms
Physical performance
Mental performance
Sleep
Mental performance
People living at 4000 m
More arithmetic errors
Reduced attention span
Increased mental fatigue
Night vision reduced at 2000 m and decreased by 50% at 5000 m
Sleep
Impaired at high altitude -frequent awakenings, unpleasant dreams, no feeling of refreshment
Periodic breathing is probably the cause
This results from instability of respiratory control systems: hypoxia versus hypocapnia
Increased ventilation to take in more O2 drives of CO2, fall in arterial PCO2 reduces drive to breath
Low levels of PO2 in blood after periods of apnea result in arousal
Reinhold Messner
climbing Everest without oxygen
-measured blood gases
-only 22ml of mercury and PCO2 became 7.5 (normal is 40)
Acid base changes
Hyperventilation reduces PCO2 blood
CO2 + H2O -><- HCO3- + H+
This results in blood and CSF becoming more alkaline
HCO3- is moved out of CSF to blood
Over 2-3 days kidneys excrete HCO3- to move the balance closer to normal
Slower adaptations
Lowlanders living at high altitude for longer periods and highlanders (born and bred) have increased numbers of erythrocytes and hence increased blood oxygen carrying capacity.
But this develops over several weeks
During short visits to high altitude this does not play a role
A transient increase in erythrocyte concentration occurs through reduction of plasma volume
High altitude diseases
Acute Mountain Sickness
High Altitude Pulmonary Edema
High Altitude Cerebral Edema
damage to capillary wall from
hydrostatic pressure
What about birds?
Birds have the highest rate of O2 consumption relative to body weight
Flight is energetically very expensive
Common house sparrow is unaffected by atmospheric pressures equivalent to 6000 m
Did evolution make a mistake with mammals
Aerodynamic valving ensures air passes in only one direction through birds’ lungs
bird adaptations
uniquely thin blood gas barrier
powerful hearts
Cx26
: a CO2-gated receptor that releases ATP
elepants under water
-high pressure in abdomen
-doesnt have pleura cavity because they snorkel underwater The large pressure across the capillary wall ~150 mmHg risks rupturing the microvessels in the pleura
In elephants the pleural space is filled with dense connective tissue
tes pleural space
in mammals is lubricated by pleural fluid so that the two faces of the pleura can slide past each other
This fluid is derived from microvessels which are fragile
tes pleural space
in mammals is lubricated by pleural fluid so that the two faces of the pleura can slide past each other
This fluid is derived from microvessels which are fragile
