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 and chronic heart failure. These agents inhibit the intracellular hydrolysis of cyclic AMP, thereby promoting cyclic AMP-catalysed phosphorylation of sarcolemmal calcium channels and activating the calcium pump. 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-adrenoceptor agonists, does not compromise the efficacy of phosphodiesterase inhibitors. The effectiveness of these new agents is, however, dependent upon some degree of basal adenylate cyclase activity.