MDL 72567, a Dihydropyridine Calcium-Antagonist, That Causes Vasodilation and Direct Sinus Bradycardia

Abstract

MDL 72567 (2,6 dimethyl,3 methoxycarbonyl,4-(2-nitrophenyl), 5-(2-furoyl)1,4 dihydropyridine) was a potent antagonist of Ca2+-induced contractions in K+-depolarized taenia preparations from the guinea pig caecum (pA2 8.8 +/- 0.1). MDL 72567 was a potent displacer of [3H]nitrendipine binding from rat cortical membrane preparations (Ki 3.99 nM), indicating an effect at the dihydropyridine binding site, which is consistent with the finding that the inhibitory effects of MDL 72567 in smooth muscle were prevented by the dihydropyridine Ca2+ channel activator Bay K 8644. MDL 72567 slowed spontaneously beating rat atria preparations to a greater extent than did nifedipine, however, for a given negative inotropic effect. Furthermore, in pithed rat preparations infused with angiotensin II to elevate blood pressure, the hypotensive effects of MDL 72567 (3 nmol/kg-3 mumol/kg, intravenously, i.v.) were accompanied by bradycardia, whereas nifedipine, PY 108-068, and nicardipine lowered blood pressure without affecting heart rate. When compared with nifedipine, MDL 72567 caused less reflex tachycardia for a given fall in blood pressure, in anesthetized beagles and in conscious renal hypertensive dogs. In anesthetized dogs, MDL 72567 increased cardiac contractility at all hypotensive doses tested (30-3,000 nmol/kg, i.v.), whereas nifedipine caused profound myocardial depression at higher doses (1,000-3,000 nmol/kg, i.v.) even though the compounds had equivalent vasodilator effects. Thus, although MDL 72567 appears to cause a direct myocardial slowing that can partially offset reflex tachycardia, the compound has negligible negative inotropic effects and may therefore be useful in angina pectoris or even in congestive heart failure.