CARDIAC UNIT: EXCITATION-CONTRACTION COUPLING

Question 1

Define: Frank-Starling Mechanism

Answer 1

physiological principle that explains how the heart responds to changes in venous return

Question 2

Define: positive inotropes

Answer 2

drugs or substances that increase myoocardial contractility (force); enhance intracellular calcium levels leading to stronger and more efficient contractions

Question 3

List 4 positive inotropes

Answer 3

• noradrenaline
• adrenaline (epinephrine)
• amphetamines - cocaine
• digitalis (digoxin)

Question 4

Explain how noradrenaline is a positive inotrope

Answer 4

Noradrenaline: acts on alpha and beta adrenergic receptors; increases blood pressure and contractility

Question 5

Explain how adrenaline (epinephrine) is a positive inotrope

Answer 5

Adrenaline (epinephrine): acts on alpha and beta adrenergic receptors; increases heart rate, contractility, and systemic vascular resistance

Question 6

Explain how amphetamines like cocaine is a positive inotrope

Answer 6

Amphetamines - cocaine: block reuptake of neurotransmitters; increased release of norepinephrine which increases heart rate and contractility

Question 7

Explain how digitalis (digoxin) is a positive inotrope

Answer 7

Digitalis (digoxin): medication derived from foxglove plant; inhibits sodium-potassium pump which indirectly increases intracellular calcium levels and thus increases force of cardiac contractions

Question 8

Define: negative inotrope

Answer 8

Negative inotropes: drugs or substances that decrease myocardial contractility (force)

Question 9

List 3 negative inotropes

Answer 9

• propranolol
• nifedipine
• acetylcholine

Question 10

Explain how propranolol is a negative inotrope

Answer 10

Propranolol:
inhibits sympathetic nervous system

beta blocker (both beta-1 and beta-2 adrenergic receptors); blocks the effects of adrenaline (epinephrine) and norepinephrine on beta-adrenergic receptors.

Question 11

Explain how nifedipine is a negative inotrope

Answer 11

Nifedipine: calcium channel blocker, specifically L-type calcium channels; inhibits movement of calcium ions into cardiac muscle cells

Question 12

Explain how acetylcholine is a negative inotrope

Answer 12

Acetylcholine: bind to muscarinic receptors, specifically M2 receptors, on the surface of cardiac myocytes; muscarinic receptors activate a signalling pathway that decreases cAMP concentration in the cell which in turn decreases intracellular calcium concentrations

Question 13

define: inotropy

Answer 13

Inotropy: force of contraction

Question 14

define: chronotropy

Answer 14

Chronotropy: rate of heart beating

Question 15

define: dromotropy

Answer 15

Dromotropy: rhythmically of contraction

Question 16

How is force of contraction regulated in the cardiac muscle that is fundamentally different from skeletal muscle?

Answer 16

In cardiac muscle the amount of calcium that enters the cell dictates the amount of sarcoplasmic reticulum that releases into the cell so that is how it regulates force of contraction

Question 17

How is calcium returned back to the sarcoplasmic reticulum?

Answer 17

SERCA uses ATP to drive calcium back into the sarcoplasmic reticulum. The pump is regulated by phospholamban (PLB).

Question 18

How is calcium returned back to the ECF for another depolarization event to occur?

Answer 18

Sodium calcium exchanger: moves calcium back out to ECF; 3 sodium in and 1 Ca2+ out

Question 19

Explain does the sympathetic nervous system increase the force of contraction?

Answer 19

• When the sympathetic nervous system is activated (often referred to as the “fight or flight” response), it releases the neurotransmitter norepinephrine onto the SA node.
• Norepinephrine binds to beta-adrenergic receptors on the surface of SA node cells.
• Activation of these receptors leads to the activation of adenylyl cyclase, an enzyme that produces cyclic adenosine monophosphate (cAMP) from ATP.
• cAMP binds to HCN (in sinoatrial node cells) and PKA (in myocytes)
• Once cAMP binds to PKA, the enzyme undergoes a conformational change that causes its regulatory subunits to dissociate from its catalytic subunits. This separation of subunits activates the catalytic subunits, which are responsible for phosphorylating target proteins (PLB, Cav1.2, TnI, RyR).
  • PLB: phosphorylation of PLB removing it from SERCA and thus removing the break on SERCA and increasing SERCA2A activity
    —–> Faster relaxation and more sarcoplasmic reticulum release
    —–> This leads to faster relaxation between beats and more sarcoplasmic Ca2+ release!
  • Cav1.2: Phosphorylation of Cav1.2 increases opening probability of Cav1.2 and Ca2+ entry
  • RyR: phosphorylation of RyR increases opening probability and thus increasing Ca2+ release from sarcoplasmic reticulum
  • TnI: PKA phosphoylates Tni decreasing the affinity of TnC site II for Ca2+ which promotes faster relaxation. Ca2+ gets unbound from TnC faster

This sympathetic stimulation thus increases the rate at which the SA node generates electrical impulses, resulting in a faster heart rate.

Question 20

How does PKA impact the force and Ca2+ graph?

Answer 20

Ca2+ is more peakier and also greater downward slope (as Ca2+ unbinds from TnC faster and can be reuptaken into SR faster too!

Force production is greater but shorter.

Question 21

Explain does the parasympathetic nervous system decrease the force of contraction?

Answer 21

• When the parasympathetic nervous system is activated (often referred to as the “rest and digest” response), it releases the neurotransmitter acetylcholine onto the SA node.
• Acetylcholine binds to muscarinic receptors on the SA node cells.
• Activation of these receptors inhibits adenylyl cyclase, reducing cAMP levels.
  Lower cAMP levels mean less activation at HCN channel and PKA
• HCN channels are now less permeable to sodium ions, less likely to pass an inward current. SA node depolarizes more slowly leading to slower heart rate.
• Key note: Parasympathetic stimulation = decreased contractility; modulates (counteracts) sympathetic regulation

Question 22

Name three pharmacological agents that regulate contractility of the heart, and briefly describe their mechanisms of action.

Answer 22

1. Sympathomimetics: stimulate sympathetic nervous system;
   - Cocaine: block reuptake of neurotransmitters; increased release of norepinephrine which increases heart rate and contractility
   - Amphetamines: release neurotransmitter from stored vesicles

Sympatholytics: inhibit the sympathetic nervous system
- Beta blockers (e.g. propranolol): beta blocker (both beta-1 and beta-2 adrenergic receptors); blocks the effects of adrenaline (epinephrine) and norepinephrine on beta-adrenergic receptors.

Digitalis (digoxin): medication derived from foxglove plant; inhibits sodium-potassium pump which indirectly increases intracellular calcium levels and thus increases force of cardiac contractions

Question 23

How does digitalis work?

Answer 23

Inhibition of sodium-potassium pump causes elevated intracellular sodium concentration
Remember, sodium is also coming in from NCX pump
- But as intracellular sodium concentraiton increases, sodium influx decreases as concentration gradient reduces. Now there is less Ca2+ extrusion
- This causes NCX to reverse and sodium will now go out and calcium will now come in.

Reduced intracellular potassium concentration
- Membrane potential increases