Electrical and Molecular Mechanism & Autonomic Control of CVS

Question 1

What is the resting membrane potential of cardiomyocytes set by and how?

Answer 1

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.

Question 2

Does the resting membrane potential equal the equilibrium potential of potassium, why?

Answer 2

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.

Question 3

What does it mean for cardiomyocytes to be electrically active?

Answer 3

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.

Question 4

What are the 4 stages of cardiomyocytes’ action potentials?

Include voltages and timings.

Answer 4

1. Opening of V-gated Na+ channels leads to influx and upstroke, from -70 to +20mV.
2. Initial depolarisation due to transient V-gated K+ channels causing efflux (Na+ channels inactivated) to just above 0mv.
3. Opening of L-type VOCC, result in plateau (CICR- crosses 0) with balance of K+ efflux for 100ms.
4. Repolarisation as Ca2+ channels inactivate and K+ efflux continues back to -85 mV.
   From 200-450ms - shape.

Question 5

How come pacemaker cells at the SAN don’t need nerve impulses to stimulate them?

Answer 5

Specialised mulches don’t sit at rest.

Question 6

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)?

Answer 6

Aka funny current - initial slope to threshold from -60 to -40mV - influx of Na+ through HCN channels.
Hyperpolarisation-activated Cyclic Nucleotide-gated channels.

Question 7

What happens when the pacemaker potential reaches threshold - the rest of the SAN action potential?

Answer 7

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.

Question 8

Action potential waveform varies throughout the heart, why does the SAN set the rhythm/act as the pacemaker?

Answer 8

Although other parts of the conducting system also have automaticity, they are slower to depolarise.

Question 9

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?

Answer 9

Bradycardia
Tachycardia
Asystole
Fibrillation - causes loss of cardiac output.

Question 10

What are the plasma concentration ranges of normal potassium, in hyperkalaemia and in hypokalaemia?

Answer 10

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

Question 11

Why are cardiomyocytes so sensitive to changes in the concentration of potassium?

Answer 11

Potassium permeability dominates the resting membrane potential of cardiomyocytes and the heart has multiple types of K+ channel, some of which may behave peculiarly.

Question 12

Explain the effects of hyperkalaemia including some risks.

Answer 12

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.

Question 13

How might hyperkalaemia be treated?

Answer 13

Calcium gluconate or insulin + glucose - won’t work if heart has already stopped.

Question 14

What happens in hypokalaemia and what are the problems?

Answer 14

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.

Question 15

Briefly describe excitation-contraction coupling in cardiac muscle.

Answer 15

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.

Question 16

What is the tone of blood vessels controlled by?

Answer 16

The contraction and relaxation of vascular smooth muscle cells (in tunica media present in arteries, arterioles and veins).

Question 17

Briefly describe excitation-contraction coupling in vascular smooth muscle.

Answer 17

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).

Question 18

Wants the purpose of the autonomic nervous system?

Answer 18

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.

Question 19

What decides whether a part of the ANS is included in the sympathetic or parasympathetic division?

Answer 19

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.

Question 20

When are the parasympathetic and sympathetic nervous systems in use?

Answer 20

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.

Question 21

What makes sweat glands and the adrenal medulla exceptions?

Answer 21

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.

Question 22

How can the sympathetic nervous system exert an effect on the heart and not simultaneously stimulate the GI tract?

Answer 22

Sympathetic drive to different tissues is independently regulated, so rather than a coordinated response triggered by fight or flight, sympathetic activity can be separate.

Question 23

What does the ANS control in the CVS and what are its limits?

Answer 23

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.

Question 24

Where does parasympathetic input to the heart come from and go to?

Answer 24

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.

Question 25

What receives the acetylcholine that the sympathetic post ganglionic nerves release at the heart and what effect does it have?

Answer 25

ACh acts on M2 receptors with a negative chronotropic effect and a decreased AVN conduction velocity.

Question 26

Describe the sympathetic input to the heart and its effects.

Answer 26

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.

Question 27

The cardiovascular centre of the medulla oblongata in the brain stem receives afferents from what?

Answer 27

Baroreceptors which measure arterial blood pressure in the arch of the aorta and in the carotid sinus (and atrial receptors - low pressure receptors).

Question 28

How does sympathetic activity speed up the pacemaker potential slope and how does parasympathetic activity slow it down?

Answer 28

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.

Question 29

How does noradrenaline increase the force of contraction? (3 ways)

Answer 29

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+.

Question 30

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.

Answer 30

Erectile tissue.

Skeletal and coronary muscle vasculature/liver.

Question 31

How does vasomotor tone allow for vasodilation and vasoconstriction?

Answer 31

Increased sympathetic output = constriction and decreased = dilation at arterioles.

Question 32

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?

Answer 32

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.

Question 33

What affect does activating B2 receptors in the vasculature have and why?

Answer 33

Vasodilation - GalphaS increases cAMP, so PKA can phosphorylate K+ channels to open and inhibits MLCK, leading to relaxation of smooth muscle.

Question 34

What affect does activating alpha1 adrenoreceptors have in the vasculature and why?

Answer 34

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.

Question 35

Active tissues produce more metabolites, name some and state their general effect on vessels.

Answer 35

Adenosine, K+, H+ - local increases have a strong vasodilator effect.

Question 36

How does the effect of metabolites compare to that of activating B2 receptors?

Answer 36

Metabolites are more important for ensuring adequate perfusion of skeletal and coronary muscle, than the activation of beta2 receptors.

Question 37

What are baroreceptors and atrial receptors?

Answer 37

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.

Question 38

What is the baroreceptor reflex good for and when is it inappropriate?

Answer 38

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.

Question 39

What are the 3 types of drugs that act on the ANS?

Answer 39

Sympathomimetics
Adrenoreceptor antagonists
Cholinergics

Question 40

What are the cardiovascular uses of sympathomimetics/ alpha or beta adrenoreceptor agonists?

Answer 40

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.

Question 41

State the use of adrenoreceptor antagonists.

Answer 41

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.

Question 42

What are the uses for cholinergics (muscarinic agonists/antagonists)?

Answer 42

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.