Pharmacology of positive inotropic phosphodiesterase III inhibitors

Cardiac phosphodiesterase III (PDE) inhibitors derived from pyridinone, imidazolone, pyridazinone and related structures form a new class of positive inotropic vasodilator agents (e.g. milrinone) 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. Drugs such as milrinone have a wider therapeutic index than 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-adrenoceptor agonists, does not compromise the efficacy of PDE inhibitors. The effectiveness of these new agents is, however, dependent upon some degree of basal adenylate cyclase activity. Individual PDE inhibitors differ in terms of both chronotropic and extracardiac properties. The reasons for this are not yet fully understood.