PCA 50941, a novel Ca2+ channel agonist

PCA 50941 is a novel 1,4-dihydropyridine derivative. Its vasoconstricting effects prompted a systematic comparison with the prototypic Ca2+ channel activator, Bay K 8644. The two compounds exhibit marked analogies and differences in their cardiovascular profiles. PCA 50941 exhibits a pronounced vascular over cardiac selectivity while Bay K 8644 has both potent vasoconstrictor effects and strong cardiac positive inotropic actions. PCA 50941 exhibits either poor positive inotropic effects (isolated guinea-pig atria) or clear negative inotropic effects (isolated perfused rat heart). Both compounds reduced by 10-40% the coronary flow in the perfused rat heart. However, PCA 50941 had slight vasoconstrictor effects in pig coronary arteries, causing their relaxation at nanomolar/micromolar concentrations; this contrasts with the almost pure, marked vasoconstrictor effects of Bay K 8644 in coronary arteries. In the rat aorta PCA 50941 exhibited a biphasic pattern of vasoconstriction and vasorelaxation, and in portal vein it markedly reduced the Ca(2+)-evoked contractions; Bay K 8644 behaved as a pure vasoconstrictor in these two preparations. It is concluded that the racemic compound, PCA 50941, exhibits different degrees of Ca2+ agonism and Ca2+ antagonism by acting upon 1,4-dihydropyridine receptors of different cardiovascular tissues. Its tissue selectivity and its prolonged duration of action give PCA 50941 a cardiovascular profile more favourable than that of other 1,4-dihydropyridine Ca2+ agonist existing to date.