Antifibrillatory Action of Bretylium: Role of the Sympathetic Nervous System

Abstract

This study was performed to assess the role of cardiac sympathetic nerves in the in vivo antifibrillatory action of bretylium using the technique of electrically induced ventricular fibrillation. An initial study determined that 3 mg/kg of nortriptyline, an adrenergic amine uptake inhibitor, was sufficient to prevent the adrenergic neuron blockade produced by 5 mg/kg of bretylium in pentobarbital anesthetized dogs. Electrical ventricular fibrillation threshold (VFT) was then determined in two groups of pentobarbital anesthetized dogs using gated trains of increasing current applied to the epicardial surface of the right ventricle during atrial pacing. After determination of an initial VFT in both groups, one group of dogs (n = 8) received 3 mg/kg nortriptyline, the other group received saline (n = 9). The VFT was redetermined in both groups, after wich all dogs received 5 mg/kg of bretylium, intravenously, and VFT was then measured at 15 and 90 min after bretylium. In saline-treated dogs, bretylium produced a significant increase in VFT from a control value of 6.9 ± 1.6 mA (X ± SEM) to 31.0 ± 0.5 mA at 15 min (p < 0.05) and 45.1 ± 4.8 mA at 90 min (p < 0.05). In nortriptyline-treated dogs, however, nortriptyline itself produced an increase in VFT which was reversed by bretylium, and VFT after bretylium was not significantly elevated until 90 min to a value of 25.2 ± 9.6 mA (control: 5.2 ± 0.9 mA). These data demonstrate that pretreatment with nortriptyline attenuates and delays the onset of the acute antifibrillatory effect of bretylium and suggests a role for the cardiac adrenergic neuron as a potential target for part of the beneficial effects to be derived from antifibrillatory drugs.

Ventricular Arrhythmias and Sudden Cardiac Death in End-Stage Renal Disease Patients on Chronic Hemodialysis

“…Cardiac sympathectomy, β-blockers, and nortriptyline (an adrenergic amine uptake inhibitor) raise the VF threshold and protect against the development of VF during coronary occlusion [68, 69]. Although there are substantial animal data relating activation of the SNS to the occurrence of VF, the data in humans are largely circumstantial.…”

The Effect of Haloperidol on Ventricular Fibrillation Threshold in Pigs

“…In comparison, lidocaine and bretylium have been reported to increase VFT as much as 370% and 554%, respectively, in dogs (Kniffen et al 1974;Kopia & Lucchesi 1987). Rather than facilitating the development of ventricular fibrillation, haloperidol significantly increased VFT (making it more difficult to induce ventricular fibrillation).…”

“…Haloperidol increased VFT in all animals studied (mean increase 30%, range 1140%). In comparison, lidocaine and bretylium have been reported to increase VFT as much as 370% and 554%, respectively, in dogs (Kniffen et al 1974;Kopia & Lucchesi 1987). Adrenergic P-receptor blocking agents have been shown to increase VFT as much as 437% in dogs (Nanas & Kralios 1986).…”

Selective inhibition of K+ ‐stimulation of Na,K‐ATPase by bretylium

“…Its prominent electrophysiological effects observed in vitro at concentrations in the 10--10-4moll1' range, are prolongation of action potential duration (APD) and effective refractory period (ERP) without any slowing of conduction (Wit et al, 1970;Bigger & Jaffe, 1971;Cardinal & Sasyniuk, 1978;Heissenbutel & Bigger, 1979). Although such effects may be of some relevance in explaining its salutary antifibrillatory action, little is known about the underlying cellular/biochemical mechanisms involved (Bacaner et al, 1986;Kopia & Lucchesi, 1987).…”