Cardiovascular Effects of the Metabolites of Diltiazem in Dogs

Abstract

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 M. (M). In the anesthetized dog. diltiazem and its metabolites produced a dose-dependent increase in coronals blood How. decreases in blood pressure and heart rate, and an increase in left ventricular dPdtmax. The ranking of coronary-vasodilating activity of diltiazem and its metabolites, in decreasing order, was diltiazem. M1. MA. M2. M4. and M. The effects of the metabolites were more selective for coronary vasodilation than for hypotension, but their selectivities were less than that of diltiazem. Coronals vasodilation and hypotension with diltiazem and M were of longer duration than those with their corresponding desacetyl metabolites. By close arterial administration to the blood-perfused canine papillary muscle preparation, diltia/em 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 diltia/em's metabolites arc qualilativeh the same as those of diltiazem. but the activity of diltiazem is the most potent, and MA is less active than M1.