Mechanism of the effect of bretylium on the ventricular fibrillation threshold in dogs

Abstract

Experiments were performed to determine the importance of sympathetic blockade vs a direct myocardial effect as a mechanism for the antifibrillatory action of bretylium. The ventricular fibrillation (VF) threshold was determined in open-chest, anesthetized dogs by scanning the vulnerable period with either a single electrical stimulus (10 ms) or a train of electrical stimuli (14 pulses, 4 ms, 100 Hz). Using the train-of-pulses technique, the VF threshold increased from 6.8 ± 0.6 mA to 29.7 ± 6.4 mA 15 minutes after a 10-mg/kg intravenous bolus of bretylium (p < 0.001, n = 8). There was no further significant change in the train-of-pulses VF threshold at 2 or 4 hours. Beta-adrenergic blockade with timolol (0.2 mg/kg) increased the train-of-pulses VF threshold from 6.7 ± 1.6 mA to 24.5 ± 5.2 mA (p >; 0.01 n = 8) and prevented any further significant change in response to bretylium. When single electrical pulses were used to scan the vulnerable period, bretylium at doses of 10 mg/kg (n = 8) and 100 mg/kg (n = 6) did not alter the VF threshold over a 4-hour observation period. The administration of timolol, alone or in combination with bretylium, did not significantly alter the single-pulse VF threshold. The failure of bretylium to alter the single-pulse VF threshold was not dependent on the site of stimulation. Stimulation of the right sympathetic cardiac nerves showed that 15 minutes of bretylium treatment was sufficient to completely inhibit adrenergic neuronal transmission to the myocardium. The data indicate that bretylium has little direct antifibrillatory action on the normal canine myocardium. The ability of bretylium to elevate the VF threshold determined with a train of stimuli appears to be primarily a result of adrenergic neuronal blockade.