Yohimbine-precipitated clonidine withdrawal: an experimental model of the antihypertensive drug withdrawal syndrome.
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 micrograms.kg-1.day-1), an alpha 2-adrenergic receptor agonist, was administered to rats via indwelling osmotic minipumps for 7 days. Withdrawal was precipitated by an intravenous injection of the alpha 2-adrenergic receptor antagonist yohimbine under alpha-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 micrograms/kg in 10 microL 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Penning
D H
DH
Department of Anaesthesia, Faculty of Medicine, Queen's University, Kingston, Ont., Canada.
Jhamandas
K
K
D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects*; D001285:Atropine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000502:physiology; D002794:Choline / Q000037:antagonists & inhibitors / Q000502:physiology; D003000:Clonidine / Q000009:adverse effects*; D005728:Ganglia, Sympathetic / Q000187:drug effects / Q000502:physiology; D005730:Ganglionic Blockers / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D018738:Hexamethonium; D006584:Hexamethonium Compounds / Q000494:pharmacology; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D015016:Yohimbine / Q000494:pharmacology*
D000959:Antihypertensive Agents; D005730:Ganglionic Blockers; D006584:Hexamethonium Compounds; D015016:Yohimbine; D018738:Hexamethonium; D001285:Atropine; D003000:Clonidine; D002794:Choline