Slow channel calcium activators, a new group of pharmacological agents.

Specific calcium channels in myocardium and vascular smooth muscle and pharmacologic agents which possess the ability to block them have been the subject of intense research over the past several years. Many studies have utilized dihydropyridine derivatives (e.g. nifedipine, nitrendipine, nisoldipine) which have been shown to be efficacious inhibitors of calcium influx through voltage sensitive slow channels. Administration of these agents results in vascular smooth muscle relaxation and negative inotropic effects. Recently, novel dihydropyridines such as Bay k 8644, CGP 28 392 and YC-170, with actions diametrically opposed to those of compounds typified by nifedipine have been synthesized. These agents demonstrate vaso-constrictor and positive inotropic effects - actions which might be expected of compounds capable of stimulating the transmembrane influx of calcium into vascular smooth muscle and myocardium. Actions of Bay k 8644 and CGP 28 392 studied in vitro and in vivo have also shown that pharmacological blockade of beta or alpha adrenergic receptors does not influence the direct effects of these agents. Future analogs, with similar but more selective actions on myocardial calcium channels, may prove useful in the management of pathologic states characterized by insufficient contractile function of the heart.