In vitro and in vivo vasodilatory activity of barnidipine and its enantiomers

Barnidipine, (3'S)-1-benzyl-3-pyrrolidinyl methyl (4S)-2,6-dimethyl-4-(m-ni trophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, is a dihydropyridine calc ium antagonist with asymmetric carbons at the dihydropyridine C-4 and the p yrrolidine C-3' positions. In this study, the vasodilatory activity of barn idipine and its 3 optical isomers were compared in vitro and in vivo to ass ess the steric effects of these asymmetric carbons. All these enantiomers p roduced concentration-dependent relaxation on KCl (40 mM)-induced contracti ons in isolated guinea pig aorta with a potency order of barnidipine>(3'R,4 R)congruent to(3'R,4S)>(3'S,4R), The potency ratio between barnidipine and the (3'S,4R) enantiomer was 118, All enantiomers increased coronary blood f low after intra-arterial administration to anesthetized coronary-perfused d ogs. The potency order almost agreed with that obtained in vitro, although the potency ratio between barnidipine and the (3'S,4R) enantiomer was only 15, These 4 enantiomers showed stereoselectivity for time course changes as well. The onset and disappearance of blood flow increase after intracorona ry administration of barnidipine were slower than those of other enantiomer s, The duration for barnidipine was longer than those for other dihydropyri dine calcium antagonists such as nifedipine or nitrendipine, The present st udy suggests stereoselectivity for the C-4 dihydropyridine and to a lesser degree for the C-3' of pyrrolidine in an ester moiety. The steric effects o f these carbons were observed not only in the potency of vasodilatory activ ity but also in its duration.