4) ANS in the CVS Flashcards
Describe the events between excitation -> contraction?
AP fired -> increase Ca2+ -> Actin and myosin interactions (see ToB)
How is the resting membrane potential set?
Via permeability of K+ ions - channels open, K+ leaves the cell down the conc. gradient (small permeability to other ions hence Ek not met)
Na+K+ATPase pump sets the gradients for the membrane potential and only contributes 5-10mV to the potential (electrogenic pump)
Describe the ventricle action potential?
1) Open V-gated Na+ channels (increase permeability to Na+) trying to reach ENa = depolarisation
2) K+ channels open briefly -> transient outward K+ current (initial repolarisation -> quick inactivation of these channels
3) Open L-Type Ca2+ v-gated channels (some K+ channels open also)
= PLATEAU - balance between EK and ECa
4) Repolarisation due to inactivation of Ca2+ channels and v-gated K+ channels open - k+ efflux
5) RMP reached with background K+ channels open
Describe the action potential sent by SAN pacemaker cells?
1) Unstable RMP - PACEMAKER POTENTIAL (aka funny current) - HCN channels open (via hyperpolarisation) allow Na+ influx
2) Threshold is reached - HCN channels inactivated
3) Ca2+ v-gated channels open - depolarisation upstroke
4) Opening of V-gated K+ channels for repolarisation
Importance of cAMP in regards to HCN channels?
cAMP -> PKA -> HCN channels phosphorylated -> operate to allow Na+ to enter
Low cAMP -> less HCN channels operating -> slower depolarisation as pacemaker potential is shallower and slower = Low HR
(Parasympathetic effect - M2 - Gi protein)
Properties of the SAN? (2)
1) Sets the rhythm of the heart
2) Depolarises faster - forcing other pacemakers to depolarise quicker e.g AVN or Purkinje have slower automaticity and are overriden. In the absence of SAN - other pacemakers take over
Describe histological features of cardiac cell? (4)
1) Intercalated disks join cells at Z lines
2) Gap junctions allow movemet of ions and electrical coupling
3) Single central cell nuclei, striated cells, branched
4) Desmosomes fix cells together
How to increase intracellular Ca2+ for cardiac cells?
Depolarisation -> L Type Ca2+ channels open -> Local calcium conc. increases via entry through T tubules -> Opens CICR channels (Ryanodine receptor) in SR -> higher levels of calcium for contraction -> sliding filament theory
How to regulate myocyte contraction? (3)
Return Ca2+ resting levels via…
1) SERCA - pump most Ca2+ into the SR (^Ca2+ leads to ^Pumping)
2) NCX
3) PMCA on the sarcolemma
Describe histological features of smooth muscle? (3)
1) Not striated, fusiform, criss cross actin and myosin filaments
2) Held by gap junctions for electrical coupling
3) No T tubules
Describe the process of smooth muscle cell contraction?
1) Ca2+ enters via L Type Ca2+ channels OR GPCR’s send Gq to send IP3 signal to release Ca2+ from SR
2) 4 Ca2+ molecules bind to 1xCalmodulin -> activates MLCK
3) MLCK phosphorylates myosin head light chain to allow actin interation via the hydrolysis of ATP -> contraction
4) MCLP used to dephosphorylate myosin head light chain -> myosin head inactivated
Regulation smooth muscle cell contraction?
MYOSIN head -
^MLCK = ^Phosphorylated myosin head light chain = ^contraction
PKA inhibits MLCK -> inhibits contraction
Causes of Hyperkalaemia? (2)
K+ supplements
Renal failure (as the kidneys filter most K+ out of the body)
Beta blockers
Describe the process of hyperkalaemia (>5mM extracellularly)?
1) Disrupts conc. gradients - EK is more positive
2) Slower movement of Na+ into the cell as it’s less negative (not such a wide gradient) = depolarisation is slower
3) Slower and less steep pacemaker potential -> aiming to reach threshold
4) Na+ channels open and inactivate within the timespan to reach threshold = less Na+ influx = threshold not met = No AP fired
5) No (or slower) excitation cell to cell - AP’s spread out
6) Lowered HR -> Arrythmia -> Asystole
Describe the process of hypokalaemia?
1) Disrupted concentration gradient = EK is more negative
2) Faster movement of Na+ into the cell due to larger gradient difference and more negative in the cell - positive ion is attracted
3) Faster depolarisation due to faster/steeper pacemaker potential - threshold reached quicker
4) Faster excitation from cell to cell and AP’s are fired closer together
5) Increased HR -> Arrythmia -> Tachycardia
Causes of hypokalaemia?
B2 agonists
Increases cellular uptake of K+ via the Na+K+pump
Describe the features of the ANS?
1) 2 neurones - 1 pre and 1 post ganglion (ganglion = collection of cell bodies)
2) 3 branches - Sympathetic, Parasympathetic, (Enteric)
3) Exerts control over SM, viscera, exocrine glands (involuntary control)
Describe features of sympathetic and parasympathetic branches of the ANS?
see ToB
Why do different tissues have different adrenoreceptors? (2)
1) Allows for diversity of action
2) Allows for selectivity of drug action
Difference between nicotinic and muscarinic receptors?
Nicotinic - Ligand gated ion channel
Muscarinic - GPCR
How is noradrenaline released?
Pre ganglion release Ach -> bind to nicotinic receptors of chromaffin cells -> noradrenaline released into the bloodstream
ANS action on the heart?
Sympathetic - Positive chronotropic and inotopic (B1 adrenoreceptor)
Parasympathetic - negative chronotropic and lowers AVN conduction velocity (M2 muscarinic receptor)
ANS action on the SAN?
Sympathetic - ^cAMP -> ^HCN -> ^pacemaker potential -> ^HR
mediated by B1 adrenoreceptors results in increasing SAN action
Parasympathetic - decreases cAMP -> decreases phosphorylation of HCN -> slows pacemaker potential -> decreases HR and SAN activty
ALSO… Increase K+ conductance, cell RMP more negative, requires higher action of HCN channels to hit threshold but cAMP is limiting
3 factors that allow noradrenaline to increase the force of contraction of the heart?
1) Activates B1 adrenoreceptors -> Gs -> ^cAMP -> PKA-> ^Phosphorylation of Ca2+ channels increases Ca2+ influx during the AP = more calcium available to contraction
2) Increased uptake of Ca2+ in SR available for release
3) Increased sensitivity of contractile machinery to Ca2+
Define vasomotor tone?
- Constant activity usually to constrict vasculature
- Action of sympathetic output mediated by a1 receptors -> vasoconstriction on arteries, Arterioles, veins
(Some blood vessels have a1 and b2 receptors to determine vasomotor tone e.g liver, myocardium, skeletal muscle) - Tone allows for dilatation and increased constriction
Effect of increased and decreased sympathetic output on vasomotor tone?
DECREASE sympathetic output -> vasodilation as less NA binds to a1 -> lowers BP
INCREASE sympathetic output -> vasoconstriction as more NA binds to a1 -> increases BP
How does the a1 and b2 receptor work?
A1 -> Gq -> +Phosphlipase C -> IP3 ligand binds to receptor-> release calcium from store -> contraction of SM -> vasoconstriction
B2 -> Gs -> +Adenyly Cyclase -> cAMP -> ^PKA -> phosphorylates MLCK (inhibited) -> less contraction = vasodilatation
Describe the effects of local metabolites on vasculature?
- H+,K+, Adenosine, ^CO2 Partial pressure produced by active tissues (exercise) = have a vasodilator effect (stronger effect than adrenaline)
- Needed for adequate perfusion of skeletal and coronary muscle
ANS control on high and low blood pressure?
1) High pressure Baroreceptors found in the arch of the aorta and the carotid sinus are stretched when there’s high arterial pressure
2) Send input via vagus nerve and glossopharyngeal nerve -> Medulla
3) Medulla determines output and sends down efferent nerve fibres
4) Effect: a) decrease AP firing = decrease HR 2) Increase vasodilation = lowers BP
Low pressure - same mechanism but receptors found in wall of right atrium or in large systemic veins
Describe effects of Sympathomimetics (adrenoreceptor agonists)?
- B2 agonist e.g adrenaline used for 1) anaphylactic shock -> vasodilator -> lowers BP 2) restore function in cardiac arrest
- B1 agonist 1) Dobutamine: given in cardiogenic shock 2) Salbutamol: given for asthma to relax bronchial smooth muscle - ^air in
Describe effects of adrenoreceptor antagonists?
- A1 antagonist e.g Prazosin used for hypertension as it inhibits NA binding to a1 on smooth muscle vasculature -> vasodilation
- Non selective B1,B2 antagonist e.g Propanolol slows HR and reduced force of contraction (B1) and bronchoconstriction (B2)
- Selective B1 antagonist e.g Atenolol is given to lower HR but prevent risk of bronchoconstriction
Describe effects of Cholinergic agonists and antagonists?
- Muscarinic agonists: e.g Pilocarpine treats Glaucoma - activated constrictor papillae muscle to reduce eye pressure
- Muscarinic antagonists: e.g Atropine or Tropicamide used to increase HR and bronchial dilation and dilate pupils (for examination)
Effects of circulation adrenaline and noradrenaline on vasculature?
(Adrenaline has a higher affinity for B2 receptors)
- ^Adrenaline bind to b2 receptor = vasodilation
- ^^Adrenaline binds to b2 and a1 receptors = vasoconstriction
- ^Noradrenaline binds to a1 receptors = vasoconstriction
ANS action on different organs?
1) Skin- tone is high -> arterio-venous anastomoses and pre capillary sphincters are shut down (open for thermo regulation)
2) Skeletal muscle- tone is high at rest, during exercise vasodilator metabolites decrease tone
3) Gut- tone is low when eating due to vasodilator metabolites produced in gut tissue
4) Brain- tone is constant and not affected by sympathetic output
5) Veins- sympathetic output causes veno-constriction to allow increases blood back to the heart
What are the corresponding G proteins and effects for each adrenergic and Cholinergic receptor?
A1 - Gq: + Phospholipase C Q
A2 - Gi: -Adenyly Cyclase I
B1- Gs: +Adenyly Cyclase S
B2 - Gs: +Adenyly Cyclase S
M1- Gq: + Phospholipase C Q
M2 - Gi: -Adenyly Cyclase I
M3 - Gq: + Phospholipase C Q
