Inhibition of centrally induced ventricular arrhythmias by rilmenidine and idazoxan in rabbits

Abstract

In a model of ventricular arrhythmias of central origin, we investigated the effects of rilmenidine, an oxazoline with antihypertensive properties, and idazoxan, an imidazoline that is an antagonist of the hypotensive effects of rilmenidine. Bicuculline, a GABAA receptor antagonist, was administered intracisternally (i.c.) to produce arrhythmias in pentobarbitone anaesthetised rabbits; 10 micrograms/kg bicuculline i.c. induced polymorphic ventricular ectopic beats and ventricular tachycardia while blood pressure increased by about 50-60% and sinusal heart rate decreased by about 20%. Rilmenidine, either administered intravenously (0.01, 0.1, 1 mg/kg i.v.) or i.c. (3, 10, 30 micrograms/kg) dose-dependently prevented the occurrence of bicuculline-induced arrhythmias while, because of a lower base-line, the blood pressure values reached were less as compared to controls. Idazoxan administered i.v. (3, 10 mg/kg) had a similar action. Idazoxan i.c. (15 micrograms/kg) had no significant antiarrhythmic effect but antagonized in part the haemodynamic and antiarrhythmic effects of rilmenidine (1 mg/kg i.v.; 30 micrograms/kg i.c.). It is suggested that the antiarrhythmic effects observed with rilmenidine are mainly mediated by blunting the bicuculline-induced increase in the sympathetic nervous output to the heart and the vascular beds. These effects of rilmenidine are likely to originate both from the central and peripheral nervous system. The antiarrhythmic effects of idazoxan i.v. might be related to a blocking action on alpha 2-adrenoceptors at the level of the coronary arteries and other vascular beds.

Protective effects of centrally acting sympathomodulatory drugs on myocardial ischemia induced by sympathetic overactivity in rabbits

“…Recent experimental evidence suggests that, in addition to their antihypertensive effect of central origin, second-generation sympathomodulatory agents such as rilmenidine also present antiarrhythmic properties (9). In fact, rilmenidine was able to blunt centrally induced ventricular arrhythmias through the inhibition of sympathetic hyperactivity in an experimental model of pharmacological activation of the central nervous system with bicuculline in anesthetized rabbits (21). Moreover, rilmenidine dose-dependently inhibits adrenaline-induced arrhythmias under halothane anesthesia in dogs, acting on central imidazoline receptors (22).…”

Chronic Stress in the Development of Essential Hypertension, Role of Rilmenidine in the Treatment of Stress Induced Hypertension

“…In addition to its antihypertensive effects it has also an antiarrhythmic and anti-ischemic effect in arrhythmias of central origin 13 . These effects were proved in animal models: rilmenidine reduced severe ventricular tachyarrhythmias of central origin by decreasing the level of sympathetic activity by acting on the central imidazoline receptors 14,15,16,17 .…”

The Sympathetic Nervous System as a Target for Cardiovascular Drugs: Perspectives

“…Rilmenidine is known to lower the blood pressure by acting, to a large part, within the central nervous system by inhibiting the sympathetic tone. In the bicuculline induced arrhythmia model, rilmenidine was capable of preventing the onset of these ventricular arrhythmias efficiently and in a dose dependent manner (5). This anti-arrhythmic effect of rilmenidine was obtained regardless of whether it was administered systemically (intravenously) or centrally (intracisternally).…”

“…Are there ways of developing anti-hypertensive drugs which are also capable of preventing the risk of sudden death from ventricular arrhythmias ? Experimental models of ventricular arrhythmias of both central and peripheral origin, in each case linked to sympathetic hyperactivity were recently developed (5,6). In one of these models, bicuculline was administered centrally to tanaesthetised rabbits.…”