The Effect of a Novel Inotropic/Vasodilating Compound on the Dog Heart at Toxicological Doses

Abstract

SK&F 94120 [5-(4-acetamidophenyl)pyrazin-2(1H)-one] is a novel inotropic agent with vasodilator activity. The potential cardiotoxicity of this compound was investigated in the beagle dog. Groups of 3 male and 3 female dogs were dosed at 0, 5, 15 or 45 mg/kg/day by slow intravenous infusion for 30 days. Electrocardiography revealed a treatment-related shortening of PR interval and an increased T wave amplitude at all doses. There were no treatment-related changes in plasma CK, CK-MB or αHBDH. Pathological examination revealed changes at 15 and 45 mg/kg consisting of a dose-related increased incidence and severity of endocardial and valvular fibroplasia and haemorrhage and haemosiderin deposition in the endocardium of the left ventricle. Hypertrophy and hyperplasia of the media of the intramural arteries was also observed at these doses. Focal necrosis of the left ventricular papillary muscles and a mild periarteritis of medium sized arteries in the right atrium was noted in individual animals at 45 mg/kg. Three further dogs were infused at doses of 0.38, 1.5, 6, 24 or 96 mg/kg and haemodynamic parameters measured (mean blood pressure, heart rate, carotid dp/dt max and pre-ejection period). A significant fall in mean blood pressure and a significant increase in carotid dp/dt max and heart rate was observed within the dose range used in the toxicity study. The cardiotoxicity observed is considered to be related to these haemodynamic effects.