Pirmenol hydrochloride (CI-845) and reference antiarrhythmic agents: effects on early ventricular arrhythmias after acute coronary artery ligation in anesthetized rats.

The coronary artery-ligated rat was investigated as an experimental model for studying the effects of pirmenol hydrochloride and reference for studying the effects of pirmenol hydrochloride and reference agents on early ventricular arrhythmias. Coronary artery ligation caused 89% lethality (ventricular fibrillation) within 10 min in untreated control rats. Vagal stimulation applied during periods of high-rate ventricular tachycardia reduced sinus, atrioventricular nodal and ventricular ectopic beats, with no uncoupled ectopic beats seen during stimulation. Rats studied with composite epicardial electrodes showed continuous electrical activity throughout diastole. These factors indicate that a reentry mechanism is likely involved. Pretreatment with pirmenol afforded protection in a dose-related fashion. A dose of 1.25 mg/kg increased survival to 58%, and all rats dosed with 2.5 to 10 mg/kg survived. Suppression of ventricular fibrillation was dose related and was complete at 5 mg/kg. The pirmenol plasma levels of 1.2 +/- 0.1 microgram/ml seen after the 5 mg/kg dose are similar to plasma levels seen at clinically effective doses, as well as at doses effective in other experimental arrhythmias. The reference agent quinidine was also highly effective in this model, all rats pretreated with 5 mg/kg survived with reduced premature ventricular beats and without a single episode of ventricular fibrillation or death. Fibrillation and/or death were also reduced by the reference agents, bretylium, lidocaine, propranolol and verapamil. The high efficacy of pirmenol against early ventricular arrhythmias in this study further defines its spectrum of activity, and suggests that pirmenol may be effective in a clinical setting where a reentrant mechanism is operative.