Sat27November0445PM 42

The administration of an inotrope leads to the following effects on the cardiovascular system:

Increased automaticity of the sino-atrial node

Increased dromotropy

Accelerated lusitropy

Increased chronotropy

Increased excitability of the conducting system, and

Increased inotropy.

Which of the following is the most likely mechanism of action of this compound?

(Please select 1 option)

Increase in intracellular calcium influenced by inhibition of phosphodiesterase III

Increase in intracellular calcium influenced by a conformational change of a Gs protein This is the correct answer

Increase in intracellular sensitivity to calcium Incorrect answer selected

Inhibition of the Na-K-ATPase membrane pump

Increase in intracellular calcium resulting from an increase in IP3

Explanation

The ligand that leads to increased automaticity, increased chronotropy, increased excitability and increased inotropy on the sino-atrial node is likely to be a beta-1 adrenoreceptor agonist.However an increase in systemic vascular resistance may result from alpha-1 adrenoreceptor effects.Examples of drugs with mixed alpha and beta effects include noradrenaline, adrenaline, dopamine and ephedrine.

Examples of drugs with some beta-1 activity include adrenaline, noradrenaline, dopamine, dopexamine, dobutamine, ephedrine and isoprenaline. The beta-1 receptor is a metabotropic or G protein coupled receptor. The beta-1 agonist when binding the cell surface membrane leads to a conformational change in the Gs unit that activates a cAMP-dependent pathway and an influx of calcium into the cell.

The catecholamines also accelerate cardiac relaxation (positive lusitropy). Dromotropy is the ability to increase conduction velocity of the atrioventricular (AV) node.

An increase in intracellular calcium influenced by inhibition of phosphodiesterase III (PDIII) is a property of the inodilators. Examples include milrinone, enoximone and amrinone. Increased entry of calcium into the myoctes leads to positive inotropy. Phosophodiesterase inhibitors also increase lusitropy. The PDIIIs produce a fall in systemic and pulmonary vascular resistance as increased cAMP inhibits mysosin light chain kinase with reduced phosphorylation of vascular smooth muscle myosin.

An increase in intracellular calcium resulting from an increase in inositol tri-phosphate (IP3) is the mechanism of action of alpha-1 adrenoreceptor agonists. IP3 is a second messenger that stimulates the influx of Ca2+ into smooth muscle cells causing an increase in systemic vascular resistance. The subsequent increase in blood pressure may cause reflex bradycardia. Examples of pure alpha-1 agonists include phenylephrine and metaraminol.

Levosimendin is a novel inotrope that increases the sensitivity of myocytes to intracellular Ca2+ It produces a positive inotropy without significant change in heart rate and oxygen consumption.

Digoxin inhibits the Na-K-ATPase membrane pump of the myocardium. This inhibition promotes sodium-calcium exchange, which increases intracellular Ca2+ with resulting increased force of contraction. Digoxin has significant parasympathetic effects on the AV node causing a bradycardia. Digoxin will not have an effect on systemic vascular resistance.

Answer Statistics

1

15%

2

49%

3

22%

4

4%

5

12%

Times answered: 243