Comparative cardiovascular actions of verapamil and its major metabolites in the anaesthetised dog

Abstract

After intracoronary administration in 12 dogs verapamil exhibited considerably greater vasodilator efficacy than the metabolites nor-verapamil (D 591, N-demethylated form of verapamil), D 617 (N-dealkylated form by removal of the dimethoxyphenylethyl moiety), and D 620 (the N-demethylated analogue of D 617), relative potencies being 1, 0.22, 0.03, and 0.04 respectively. According to their coronary activity equipotent doses of the drugs were administered i.v. in another group of 24 animals and haemodynamic variables were measured. Verapamil exhibited significant effects on LVSP (−17%), systolic, mean and diastolic blood pressures (−18, −20, −24%), cardiac output (+66%), stroke volume (+ 18%), heart rate (+40%), peripheral (−51%), and coronary resistance (−60%), coronary flow (+98%), and P-Q interval (+ 15%, P-Q_c+56%). Contractility was not influenced as judged from mean values. D 591 produced significant but smaller haemodynamic effects on coronary flow (+42%), cardiac output (+25%), stroke volume (+ 18%), peripheral (−20%), and coronary resistance (−31%). Heart rate and consequently left ventricular contractility increased gradually with a time effect course different from the other variables. The only significant effects after D 617 were a reduction in contractility (−20%) and an increase in coronary resistance (+ 18%). D 620 exhibited no statistically significant haemodynamic changes. It is concluded that of the metabolites investigated D 591 may partly contribute to the haemodynamic actions of verapamil, whereas D 617 and 620 appear to play no role. None of the metabolites seems to contribute to verapamil's prolongation of nodal conduction.