Cardiovascular effects of the metabolites of diltiazem in dogs.

The effects of diltiazem and some of its metabolites on the cardiovascular system were studied in anesthetized dogs and in blood-perfused canine papillary muscles. The metabolites included N-desmethyldiltiazem (MA), a newly discovered major metabolite; desacetyldiltiazem (M1); desacetyl MA (M2); O-desmethyl M1 (M4); and O-desmethyl M2 (M6). In the anesthetized dog, diltiazem and its metabolites produced a dose-dependent increase in coronary blood flow, decreases in blood pressure and heart rate, and an increase in left ventricular dP/dtmax. The ranking of coronary-vasodilating activity of diltiazem and its metabolites, in decreasing order, was diltiazem, M1, MA, M2, M4, and M6. The effects of the metabolites were more selective for coronary vasodilation than for hypotension, but their selectivities were less than that of diltiazem. Coronary vasodilation and hypotension with diltiazem and MA were of longer duration than those with their corresponding desacetyl metabolites. By close arterial administration to the blood-perfused canine papillary muscle preparation, diltiazem and its metabolites also produced coronary-vasodilating actions, whereas the negative inotropic actions were very weak. The present study revealed that the cardiovascular properties of some of diltiazem's metabolites are qualitatively the same as those of diltiazem, but the activity of diltiazem is the most potent, and MA is less active than M1.