PCA-50941, A NOVEL CA2+ CHANNEL AGONIST

PCA 50941 is a novel 1,4-dihydropyridine derivative. Its vasoconstrict ing effects prompted a systematic comparison with the prototypic Ca2channel activator, Bay K 8644. The two compounds exhibit marked analog ies and differences in their cardiovascular profiles. PCA 50941 exhibi ts a pronounced vascular over cardiac selectivity while Bay K 8644 has both potent vasoconstrictor effects and strong cardiac positive inotr opic actions. PCA 50941 exhibits either poor positive inotropic effect s (isolated guinea-pig atria) or clear negative inotropic effects (iso lated perfused rat heart). Both compounds reduced by 10-40% the corona ry flow in the perfused rat heart. However, PCA 50941 had slight vasoc onstrictor effects in pig coronary arteries, causing their relaxation at nanomolar/micromolar concentrations; this constrasts with the almos t pure, marked vasoconstrictor effects of Bay K 8644 in coronary arter ies. In the rat aorta PCA 50941 exhibited a biphasic pattern of vasoco nstriction and vasorelaxation, and in portal vein it markedly reduced the Ca2+-evoked contractions; Bay K 8644 behaved as a pure vasoconstri ctor in these two preparations. It is concluded that the racemic compo und, PCA 50941, exhibits different degrees of Ca2+ agonism and Ca2+ an tagonism by acting upon 1,4-dihydropyridine receptors of different car diovascular tissues. Its tissue selectivity and its prolonged duration of action give PCA 50941 a cardiovascular profile more favourable tha n that of other 1,4-dihydropyridine Ca2+ agonists existing to date.