Yohimbine-precipitated clonidine withdrawal: An experimental model of the antihypertensive drug withdrawal syndrome

Abstract

In this study, a model of the clonidine withdrawal syndrome in normotensive rats was used to investigate the mechanisms and sites of the cardiovascular responses associated with this withdrawal. Clonidine (400 μg∙kg−1∙day−1), an α2-adrenergic receptor agonist, was administered to rats via indwelling osmotic minipumps for 7 days. Withdrawal was precipitated by an intravenous injection of the α2-adrenergic receptor antagonist yohimbine under α-chloralose anaesthesia, and the blood pressure and heart rate responses were recorded. Yohimbine (0.25, 0.50, and 1.0 mg/kg i.v.) in clonidine-treated rats provoked an immediate rise in blood pressure and heart rate. Similar injections in saline-treated rats produced slight hypotension and modestly increased the heart rate. Intracerebroventricular (i.c.v.) yohimbine injection (30 or 120 μg/kg in 10 μL volume) failed to elicit signs of withdrawal in clonidine-treated animals, but a subsequent intravenous injection of yohimbine (0.5 mg/kg) provoked brisk signs of withdrawal. Hexamethonium (2 mg/kg) pretreatment did not abolish the increase in the heart rate, but it delayed the blood pressure increase. Pretreatment with atropine sulfate (1 mg/kg) did not block the yohimbine-induced increase in heart rate or blood pressure. This study demonstrates that yohimbine can effectively produce cardiovascular signs of withdrawal in rats chronically exposed to clonidine. The lack of i.c.v. yohimbine suggests that the antagonist-precipitated withdrawal may not have a central origin. The failure of atropine to attenuate the blood pressure and heart rate responses, and the failure of hexamethonium to block the heart rate response and the late phase of blood pressure response, suggest that central cholinergic hyperactivity is not substantially involved in the yohimbine-precipitated clonidine withdrawal. It is suggested that under the conditions of clonidine exposure used here, the yohimbine-precipitated response may arise from increased activity of peripheral sympathetic mechanisms.Key words: yohimbine, clonidine withdrawal syndrome.