Pharmacology of bipyridine phosphodiesterase III inhibitors

The bipyridine phosphodiesterase III inhibitors amrinone and milrinone form a new class of positive inotropic vasodilator agents that are beneficial in the treatment of acute or decompensated heart failure. These agents inhibit the intracellular hydrolysis of cyclic adenosine monophosphate, thereby promoting cyclic adenosine monophosphate--catalyzed phosphorylation of sarcolemmal calcium channels and activating the calcium pump. They have a wider therapeutic index than do the cardiac glycosides. They also have vasodilator and lusitropic actions and are devoid of the central stimulant actions that narrow the therapeutic index of theophylline and other methylxanthines. Receptor down-regulation, which curtails the inotropic efficacy of beta-adrenoreceptor agonists, does not compromise the efficacy of phosphodiesterase inhibitors. The effectiveness of these new agents is, however, dependent on some degree of basal adenylate cyclase activity.