Evidence for control of cardiac vagal tone by benzodiazepine receptors

Previous work has suggested that vagal preganglionic neurons which project to the heart, are tonically inhibited by endogenous gamma-aminobutyric acid (GABA). This study tested the hypothesis that benzodiazepines, which are thought to act by enhancing GABAergic inhibition, would increase heart rate by suppressing cardiac vagal activity in anesthetized rats, and that pretreatment with Ro 15-1788, a specific benzodiazepine receptor antagonist, would prevent tachycardia induced by benzodiazepines. Midazolam (0.05-4 mg/kg i.v.), alprazolam (1 mg/kg i.v.) and chlordiazepoxide (10 and 20 mg/kg i.v.), all evoked significant increases in heart rate. Pretreatment with atropine methobromide (2 mg/kg i.v.) increased the basal heart rate and prevented tachycardia induced by benzodiazepines. Basal heart rate and blood pressure were unchanged after pretreatment with Ro 15-1788 (10 mg/kg), but subsequent administration of any of the benzodiazepines failed to elicit increases in heart rate in these animals. These findings suggest that benzodiazepines may be potent vagolytics and that this effect should be considered before these agents are administered to patients who have suffered a recent myocardial infarction, in whom vagal tone is thought to be protective against fatal ventricular arrhythmias.