Cardiac versus vascular effects of a new dihydropyridine derivative, CV-4093. In vitro comparison with other calcium antagonists

Abstract

The effects of CV-4093, a new dihydropyridine derivative, on isolated cardiovascular tissues were compared with those of several dihydropyridine and non-dihydropyridine calcium antagonists. CV-4093 effectively inhibited the contractions induced in canine femoral arteries by high [K +] 0 and Bay K 8644, but incompletely relaxed those induced by norepinephrine. CV-4093, 10 −6 M, abolished the electrically induced slow action potentials in guinea-pig papillary muscles partially depolarized by 25 mM K + solution and attenuated those induced by isoproterenol, histamine and Bay K 8644. The rank order of potency of dihydropyridine and non-dihydropyridine calcium antagonists in canine femoral arteries and veins precontracted with 120 m [K +] 0 was as follows: nisoldipine > nicardipine ⩾ nifedipine ⩾ CV-4093 > verapamil ⩾ diltiazem. Nisoldipine was the most potent and CV-4093 was the least potent among these drugs in terms of negative inotropic effect in normally polarized papillary muscles and negative chronotropic effect in right atria of guinea pigs. The rank order of potency for these cardiodepressant actions was nisodipine ⩾ nifedipine > nicardipine > verapamil > diltiazem ⩾ CV-4093. The duration of action potential in guinea-pig papillary muscles was shortened by nisoldipine and nifedipine, unchanged by nicardipine and CV-4093 and was slightly prolonged by verapamil and diltiazem. These results suggest that CV-4093 is a calcium antagonist with a highly selective vascular effect and little cardiodepressant action, and could be of value for the treatment of hypertension.