Central and peripheral cardiovascular effects of the enantiomers of the calcium antagonist PN 200-110

Abstract

The negative inotropic effects and the central and peripheral hypotensive effects of (+) and (−) PN 200-110 were investigated in cultured chick heart cells and in spontaneously hypertensive rats, respectively. There was a large difference in negative inotropic potency between the two enantiomers in cultured chick embryo ventricular cells: the (+) enantiomer was 140 fold more potent (IC 50 = 1.1 ±0.2 nM) than the (−) enantiomer (IC 50 = 160 ± 20 nM). (+) PN 200-110 was 10 fold more potent than (−) PN 200-110 in lowering blood pressure after intravenous injection and only three fold more potent after intra-cerebroventricular injection (i.c.v.) into pentobarbital-anaesthetized spontaneously hypertensive rats. I.c.v. administered (+) PN 200-110 (1 μg/kg) partially antagonized the hypertensive response to i.c.v. administered BAY K 8644 (30 μg/kg), a calcium channel agonist, while the same dose of the (−) enantiomer did not change the i.c.v. BAY-induced increase in blood pressure. These results suggest that the dihydropyridine calcium channel antagonist, PN 200-110, may act centrally and stereoselectively at the level of the dihydropyridine receptor sites involved in the control of blood pressure in spontaneously hypertensive rats.