Electrical and Molecular Mechanism & Autonomic Control of CVS Flashcards
What is the resting membrane potential of cardiomyocytes set by and how?
K+ permeability - the ions move out of the cell down their concentration gradient and the small movement of ions makes the inside negative with respect to the outside - as charge builds up, the electrical gradient is established.
Does the resting membrane potential equal the equilibrium potential of potassium, why?
No, equilibrium potential of potassium will exist when there’s no net movement of potassium, but the cardiomyocytes membrane has a very small permeability to other ion species.
What does it mean for cardiomyocytes to be electrically active?
They fire action potentials, which trigger and increase in intracellular Ca2+, which is required for actin-myosin interaction, for contraction. Action potentials in the heart are much longer than in neuronal axons.
What are the 4 stages of cardiomyocytes’ action potentials?
Include voltages and timings.
- Opening of V-gated Na+ channels leads to influx and upstroke, from -70 to +20mV.
- Initial depolarisation due to transient V-gated K+ channels causing efflux (Na+ channels inactivated) to just above 0mv.
- Opening of L-type VOCC, result in plateau (CICR- crosses 0) with balance of K+ efflux for 100ms.
- Repolarisation as Ca2+ channels inactivate and K+ efflux continues back to -85 mV.
From 200-450ms - shape.
How come pacemaker cells at the SAN don’t need nerve impulses to stimulate them?
Specialised mulches don’t sit at rest.
The first stage in the SAN action potential involves the pacemaker current, which is what?
What’s the involvement of HCN channels (what does it stand for)?
Aka funny current - initial slope to threshold from -60 to -40mV - influx of Na+ through HCN channels.
Hyperpolarisation-activated Cyclic Nucleotide-gated channels.
What happens when the pacemaker potential reaches threshold - the rest of the SAN action potential?
Opening of L-type Ca2+ channels causes influx and depolarisation (CICR) up to +15mV ish, then opening of V-gated K+ channels, with effluvia and repolarisation. The pacemaker potential/funny current is reactivated in membrane potential falls lower than -50mV. The whole thing takes 800ms.
Action potential waveform varies throughout the heart, why does the SAN set the rhythm/act as the pacemaker?
Although other parts of the conducting system also have automaticity, they are slower to depolarise.
The triggering of a single action potential, which spreads through the heart is responsible for contraction. What's it called when: Action potentials are too slow Action potentials are too quick Action potentials fail Electrical activity becomes random?
Bradycardia
Tachycardia
Asystole
Fibrillation - causes loss of cardiac output.
What are the plasma concentration ranges of normal potassium, in hyperkalaemia and in hypokalaemia?
Normal = 3.5-5.5 mmol/L
Hyperkalaemia > 5.5mmol/L mild is up to 5.9, moderate is up to 6.4 and severe is above that
Hypokalaemia < 3.5mmol/L
Why are cardiomyocytes so sensitive to changes in the concentration of potassium?
Potassium permeability dominates the resting membrane potential of cardiomyocytes and the heart has multiple types of K+ channel, some of which may behave peculiarly.
Explain the effects of hyperkalaemia including some risks.
There is a decreased driving force for K+ to leave the cells, so they are less negative inside - the equilibrium of potassium is less negative. This means that myocytes are depolarised and the upstroke of the action potential is slower - some Na+ channels are inactivated with slight depolarisation.
Risks: asystole, initial increase in excitability. Depends on extent and how quick.
How might hyperkalaemia be treated?
Calcium gluconate or insulin + glucose - won’t work if heart has already stopped.
What happens in hypokalaemia and what are the problems?
Lengthens action potential, so delays hyperpolarisation. Problems include longer action potentials leading to Early After Depolarisations (EADs), which can lead to oscillations in membrane potential, which can result in ventricular fibrillation and a subsequent loss of cardiac output - more likely o have arrhythmias if preexisting heart condition.
Briefly describe excitation-contraction coupling in cardiac muscle.
Depolarisation opens L-type Ca2+ channels in the T-tubule system - localised Ca2+ entry triggers CICR from RyR in SR - close link between 2 types of Ca2+ channels -25% Ca2+ entry across sarcolemma and 75% from SR. As with skeletal muscle, Ca2+ binds to troponinC, conformational change shifts tropomyosin to reveal myosin binding site on actin filament - sliding filament mechanism.
Cardiac muocyte relaxation - Ca2+ returns to resting levels by SERCA, NCX & sarcolemma Ca2+ATPase.
What is the tone of blood vessels controlled by?
The contraction and relaxation of vascular smooth muscle cells (in tunica media present in arteries, arterioles and veins).
Briefly describe excitation-contraction coupling in vascular smooth muscle.
Ca2+ binds to calmodulin and the complex activates MLCK, which phosphorylases the regulatory myosin light chain to permit actin interaction. Relaxation occurs as MLC phosphatase dephosphorylates MLC. MLCK itself may be phosphorylated by PKA, to inhibit it and therefore inhibit contraction.
This occurs at alpha1 receptors - G alpha q - phospholipase C –> IP3 (Ca2+ release) + DAG (PKA).
Wants the purpose of the autonomic nervous system?
It’s important for regulating many physiological functions - homeostasis, coordinating the response to stress and is largely outside voluntary control and exerts control over smooth muscle, exocrine secretion and rate and force of heart contraction.
What decides whether a part of the ANS is included in the sympathetic or parasympathetic division?
Anatomical grounds - preganglionic neurones arise from spinal chord - craniosacral/thoracolumbar. Where both the parasympathetic and sympathetic systems both innervate a tissue, they often exert opposite effects.
When are the parasympathetic and sympathetic nervous systems in use?
Sympathetic activity is increased under stressful conditions and parasympathetic activity is more dominant under basal conditions.
Both work together to achieve the balance of homeostasis.
What makes sweat glands and the adrenal medulla exceptions?
At the sweat glands, post ganglionic neurones secrete ACh to act of M3 receptors instead of NA.
Chromatin cells of the adrenal medulla act as post ganglionic neurons, releasing NA into the blood.
How can the sympathetic nervous system exert an effect on the heart and not simultaneously stimulate the GI tract?
Sympathetic drive to different tissues is independently regulated, so rather than a coordinated response triggered by fight or flight, sympathetic activity can be separate.
What does the ANS control in the CVS and what are its limits?
It controls the heart rate, force of contraction of the heart, peripheral resistance of blood vessels (arteriolar contraction) and venoconstriction.
It does not initial electrical activity in the heart, as a denervated heart still beats, but faster (100bpm), as the heart at rest is normally under vagal influence.
Where does parasympathetic input to the heart come from and go to?
Preganglionic fibres originate from the 10th/X cranial nerve - Vagus. The synapse with post ganglionic cells is on the epicardial surface or within the walls of the heart - at the AVN or SAN more likely.
What receives the acetylcholine that the sympathetic post ganglionic nerves release at the heart and what effect does it have?
ACh acts on M2 receptors with a negative chronotropic effect and a decreased AVN conduction velocity.
Describe the sympathetic input to the heart and its effects.
Post ganglionic fibres come from the sympathetic trunk and innervate the SAN, AVN and myocardium - released noradrenaline acts on mainly beta1 receptors with positive chronotropic and inotropic effects - B2 and B3 receptors also present.
The cardiovascular centre of the medulla oblongata in the brain stem receives afferents from what?
Baroreceptors which measure arterial blood pressure in the arch of the aorta and in the carotid sinus (and atrial receptors - low pressure receptors).
How does sympathetic activity speed up the pacemaker potential slope and how does parasympathetic activity slow it down?
Sympathetic - B1 GPCRs (G alpha s), increase cAMP, which is a cyclic nucleotide and so gates HCNs.
Parasympathetic - M2 GPCRs (G alpha i), decrease cAMP and increase K+ conductance, so the membrane potential is further from threshold.
How does noradrenaline increase the force of contraction? (3 ways)
Acting on B1 receptors in myocardium - more cAMP activates PKA which phosphorylates Ca2+ channels, so an increased entry during plateau of action potential.
Also increased uptake of Ca2+ in sarcoplasmic reticulum and increased sensitivity of contractile machinery to Ca2+.
Most vessels receive sympathetic innervation - name a specialised tissue with parasympathetic integration.
Most arteries and veins have alpha1 adrenoreceptors - name 2 types of vasculature that also have beta2.
Erectile tissue.
Skeletal and coronary muscle vasculature/liver.
How does vasomotor tone allow for vasodilation and vasoconstriction?
Increased sympathetic output = constriction and decreased = dilation at arterioles.
Some blood vessels, such as those at the myocardium, skeletal muscle and liver have B2 receptors, what are the effects on adrenaline in this vasculature, bearing in mind the other type of adrenoreceptor present?
Circulating adrenaline has a higher affinity for B2 receptors that a1, so at physiological concentrations adrenaline binds preferentially to them. At higher concentrations, e.g. After a shot of adrenaline, it will first bind to a1 receptors.
What affect does activating B2 receptors in the vasculature have and why?
Vasodilation - GalphaS increases cAMP, so PKA can phosphorylate K+ channels to open and inhibits MLCK, leading to relaxation of smooth muscle.
What affect does activating alpha1 adrenoreceptors have in the vasculature and why?
Vasoconstriction - GalphaQ mean IP3 production, so increased efflux of calcium from intracellular stores and a increase of extracellular calcium, leading to contraction of smooth muscles.
Active tissues produce more metabolites, name some and state their general effect on vessels.
Adenosine, K+, H+ - local increases have a strong vasodilator effect.
How does the effect of metabolites compare to that of activating B2 receptors?
Metabolites are more important for ensuring adequate perfusion of skeletal and coronary muscle, than the activation of beta2 receptors.
What are baroreceptors and atrial receptors?
Nerve ending is arch of the aorta and corotid sinus that are sensitive to stretch - increased arterial pressure stretches them. They communicate a change in state of the CVS to the brain via afferents nerves to alter the activity of efferent nerves.
What is the baroreceptor reflex good for and when is it inappropriate?
It is good at maintaining blood pressure in the short term, such as compensating for moment to moment changes when someone stands up, but baroreceptors can be reset to higher levels over time, with a persistent blood pressure increase, so it’s not effective for long term control of BP.
What are the 3 types of drugs that act on the ANS?
Sympathomimetics
Adrenoreceptor antagonists
Cholinergics
What are the cardiovascular uses of sympathomimetics/ alpha or beta adrenoreceptor agonists?
Adrenaline is administered to restore function after a cardiac arrest.
Beta 1 agonist donutamine in given in cardiogenic shock (with electricity).
Adrenaline is given after an anaphylactic shock.
B2 agonists salbutamol is used in asthma treatment.
State the use of adrenoreceptor antagonists.
Alpha1 antagonists e.g. Prazosin is an antihypertensive agent with too many side effects - only used with resistant hypertension - inhibits NA action on vascular smooth muscle leading to vasodilation.
Propranolol is a non selective B1/2 antagonist with negative chronotropic and ionotropic effects, but also acts on bronchial smooth muscle (B2 bronchoconstriction, so not for asthmatics). Atenolol is a (cardio)selective B1 antagonist, with less risk.
What are the uses for cholinergics (muscarinic agonists/antagonists)?
Pilocarpine is used in treatment of glaucoma - activates constrictor pupillae muscles. Parasympathetic like effect.
Atropine or tropicamide increases heart rate, bronchial dilation and is used to dilate pupils for an eye examination.
