Ventricle obtained from patients with congestive heart failure demonstrate marked reduction in beta-adrenoreceptor density and in myocardial contractility. This is consistent with an increase in norepinephrine that downregulates beta-receptors. The decrease in receptor density is proportional to the severity of heart failure and involves beta,, but not beta2-receptors. This might be the basis for use of low doses of beta-blockers to reverse the downregulation of beta-receptors and restore responsiveness to adrenergic inotropic stimulation. In sum, the failing myocardium becomes tolerant to prolonged exposure to catecholamines.
What is the mechanism of action of the phosphodiesterase inhibitors?
This positive inotropic agent increases availability of Ca2+ to the intracellular compartment. The beta-adrenergic mimetic drugs stimulate adenylate cyclase that then increases cAMP. cAMP phosphorylates the protein kinase which, in turn, increases the Ca2+ influx through the calcium channel. The phosphodiesterase inhibitors inhibit the degradation of cAMP, thereby limiting Ca2+ influx through the calcium channel.
What are the indications for use of amrinone?
Amrinone causes a dose-dependent increase in cardiac output and a decrease in right and left filling pressure and systemic vascular resistance.
Its effects are similar, in ways, to a combination of sympathomimetics and vasodilators. The effect of amrinone is additive to the effect of digoxin and other mimetic agents, and there is no tolerance problem as seen in other amines. Intravenous infusions are indicated for treatment for congestive heart failure refractory to digoxin and furosemide and for post-myocardial depression, for left ventricular failure in myocardial infarction, and in patients awaiting cardiac transplantation.