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.