Relative selectivity for negative chronotropic and inotropic effects of a novel dihydropyridine derivative, CD-832

Abstract

The effects of CD-832 [(4 R)-(−)-2-(nicotinoyl-amino)ethyl 3-nitroxypropyl 1,4-dihydro-2,6-dimethyl-4,3-nitrophenyl, 3,5-pyridine dicarboxylate], a novel dihydropyridine derivative, on various guinea-pig myocardial preparations were compared with those of nifedipine, verapamil and diltiazem. CD-832 decreased the action potential duration of isolated papillary muscles without substantially affecting other parameters. In voltage-clamped single ventricular myocytes, CD-832 decreased the L-type Ca 2+ current amplitude while having little effect on outward currents. CD-832 and other Ca 2+ channel antagonists produced negative chronotropic effects in isolated right atrial preparations and negative inotropic effects in right ventricular papillary muscles, respectively, in a concentration-dependent manner. The potency order for the negative chronotropic effect was CD-832 > nifedipine > verapamil > diltiazem, while that for the negative inotropic effect was nifedipine > verapamil ≥ CD-832 > diltiazem. The ratio, EC 20 for negative inotropic effect divided by EC 20 for negative chronotropic effect, which was considered to be an index of selectivity for negative chronotropic effect was highest for CD-832, the ratio for CD-832, nifedipine, verapamil and diltiazem being 5.4, 0.11, 0.25 and 0.37, respectively. These results indicate that CD-832 is an L-type Ca 2+ channel antagonist with relative selectivity for a negative chronotropic effect rather than for a negative inotropic effect. This ‘chrono-selective’ cardiosuppressive effect of CD-832 could be of value in the treatment of cardiovascular diseases such as angina pectoris.