Physiology and Pharmacology 20: (davies) autonomic control and cardiac glycosides

Question 1

Which current in SA pacemaker activity is regulated by the Sympathetic Nervous System and how?

Answer 1

If -> funny current
Modulated via cAMP

Sympathetic nerves release NA (or circulating adrenaline)

• binds to B1 adrenoceptor
• Gs coupled - activates AC - cAMP - PKA

cAMP acts directly on If channels to increase activity -> increases the rate of pacemaker depolarisation

PKA phosphorylates L-type calcium channels, increasing activity, lowering threshold for action potential

Question 2

Which current in SA pacemaker activity is regulated by the Parasympathetic Nervous System and how?

Answer 2

If -> funny current
Modulated via cAMP

Parasympathetic nerves release ACh
- act on M2 muscarinic receptors
- Gi coupled - inhibits AC - less cAMP - less phosphorylated PKA - less phosphorylation of L-type Ca2+ channels
- decreased Ca2+ entry, less cAMP
(reduction in If -> increases pacemaker slope)
(reduction in Ica -> increases threshold)

BetaGamma Gi subunit also directly activates K+ outward channels
(causes hyperpolarisation, slows rate of pacemaker depolarisation)

Mainly reduced heart rate, not much change in ventricular contraction strength

Question 3

What would you expect to happen to If activation curve in the presence of NA and ACh?

Answer 3

Addition of ACh -> decreased If channel activity -> negative shift to the left

Addition of NA -> Increased If channel actibvity -> positive shift to the right

Question 4

Why does heart rate slow quicker with parasympathetic activity in comparison to the slower sympathetic rate increase?

Answer 4

Gi protein BetaGamma subunits also activate inward rectifying K+ channels (GIRKS) -> increased hyperpolarisation of SA node cells

This direct action of GiBetaGamma is faster than the effect on If through changes in cAMP

Therefore slowing rate via parasympathetic activity faster

Question 5

How does sympathetic activity increase contractile force?

Answer 5

Sympathetic activity increases activity of PKA

PKA phosphorylates L-type Ca2+ channels

Increases AP plateau and Ca2+ entry

Increases Ca2+ release (CICR)

-> increases contractile force

Question 6

4 Major classes of cardiac drugs?

Answer 6

Autonomic drugs
Cardiac glycosides
Arrythmias and Anti-arrythmias drugs
Anti-anginals

Question 7

Main types of autonomic drugs?

Answer 7

Beta1-receptor agonists

• e.g. adrenaline, isoprenaline
• > Increases heart rate, automaticity, contractile force

Beta1-receptor antagonists (Beta-blockers)
- e.g. Propranol (B selective), Atenolol (B1 selective)
-> slow heart rate, reduce automaticity, reduce force but increase efficiency
(Will treat angina)

Muscarinic receptor antagonists
- e.g. atropine
Prevent slow of heartrate by blocking Parasympathetic ACh

Question 8

What are cardiac glycosides and how do they act? Examples?

Answer 8

Increase the output force of heart and decrease heart rate

Inhibit Sodium/Potassium ATPase

• > reduced sodium extrusion
• > lowers energy gradient for Ca2+ extrusion by Na/Ca exchange
• > increases intracellular calcium -> increased contractile force

Slows heart rate and conduction at AVN

• > slower conduction allows more ventricular filling
• > higher stroke volume -> higher force

e.g. oubain, digoxin