RELATIVE SELECTIVITY FOR NEGATIVE CHRONOTROPIC AND INOTROPIC EFFECTS OF A NOVEL DIHYDROPYRIDINE DERIVATIVE, CD-832

The effects of CD-832 [(4R)-(-)-2-(nicotinoyl-amino)ethyl 3-nitroxypro pyl 1,4-dihydro-2,6-dimethyl-4,3-nitrophenyl, 3,5-pyridine dicarboxyla te], a novel dihydropyridine derivative, on various guinea-pig myocard ial 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. I n voltage-clamped single ventricular myocytes, CD-832 decreased the L- type Ca2+ current amplitude while having little effect on outward curr ents. CD-832 and other Ca2+ channel antagonists produced negative chro notropic effects in isolated right atrial preparations and negative in otropic effects in right ventricular papillary muscles, respectively, in a concentration-dependent manner. The potency order for the negativ e chronotropic effect was CD-832 > nifedipine > verapamil > diltiazem, while that for the negative inotropic effect was nifedipine > verapam il greater than or equal to 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 negativ e chronotropic effect was highest for CD-832, the ratio for CD-832, ni fedipine, verapamil and diltiazem being 5.4, 0.11, 0.25 and 0.37, resp ectively. These results indicate that CD-832 is an L-type Ca2+ channel antagonist with relative selectivity for a negative chronotropic effe ct rather than for a negative inotropic effect. This 'chrono-selective ' cardiosuppressive effect of CD-832 could be of value in the treatmen t of cardiovascular diseases such as angina pectoris.