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-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylat e, is a dihydropyridine calcium antagonist with asymmetric carbons at the dihydropyridine C-4 and the pyrrolidine C-3' positions. In this study, the vasodilatory activity of barnidipine and its 3 optical isomers were compared in vitro and in vivo to assess the steric effects of these asymmetric carbons. All these enantiomers produced concentration-dependent relaxation on KCI (40 mM)-induced contractions in isolated guinea pig aorta with a potency order of barnidipine>(3'R,4R) approximately/= (3'R,4S)>(3'S,4R). The potency ratio between barnidipine and the (3'S,4R) enantiomer was 118. All enantiomers increased coronary blood flow after intra-arterial administration to anesthetized coronary-perfused dogs. 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 intracoronary administration of barnidipine were slower than those of other enantiomers. The duration for barnidipine was longer than those for other dihydropyridine calcium antagonists such as nifedipine or nitrendipine. The present study 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 of these carbons were observed not only in the potency of vasodilatory activity but also in its duration.