Cardiovascular effects of a new phenoxyalkylamine derivative, 2-isopropyl-5-[3-(2-methoxyphenoxy)propylamino]-2-(3,4,5-trimethoxy phenyl) valeronitrile fumarate (HV-525), in cross-circulated dog atrial preparations

Abstract

A newly developed phenoxyalkylamine derivative, 2-isopropyl-5-[3-(2-methoxyphenoxy)propylamino]-2-(3,4, 5-trimethoxyphenyl)-valeronitrile fumarate (HV-525), was investigated in intact dogs and in isolated dog atria perfused with anesthetized donor dog's arterial blood. When 0.3 mg/kg of HV-525 was intravenously administered to the donor dog, a depressor effect without significant changes in heart rate was observed in donor dogs and a decrease in developed tension was observed in the isolated atrium. At 1 mg/kg, HV-525 caused a depressor response in donor dogs and decreases in developed tension and atrial rate in isolated atria. The decrease in systemic blood pressure seen following 1 mg/kg of HV-525 was between 15-40 mmHg. These effects continued for about 60 min. When HV-525 was administered into the cannulated sinus node artery of the isolated atrium, dose related negative inotropic and chronotropic actions were observed. Occasionally, HV-525 induced slight, brief positive chronotropic and inotropic effects followed by long-lasting negative effects. The threshold dose for inducing the negative chronotropic effect was approximately 3 micrograms while the negative inotropic one was approximately 1 microgram. A large dose of 100 micrograms of HV-525 caused a profound deceleration but not atrial arrest. The order of potencies for inducing a negative chronotropic effect in dog atria was verapamil greater than propranolol much greater than HV-525 greater than or equal to lidocaine greater than or equal to quinidine greater than phenytoin greater than disopyramide greater than procainamide, and that for inducing a negative inotropic effect was verapamil greater than or equal to propranolol greater than HV-525 greater than lidocaine greater than phenytoin greater than disopyramide greater than procainamide greater than or equal to quinidine. HV-525 did not induce a significant effect on sinoatrial conduction time. HV-525 at the doses studied, uniformly suppressed the frequency-force relationship, while verapamil, one of the phenoxyalkylamine derivatives, caused a marked depression of high frequency-induced contraction. Thus, it is concluded that HV-525 has mild depressant properties on the cardiovascular system and may have characteristics different from those of verapamil.