RECEPTOR MECHANISMS FOR CLONIDINE REVERSAL OF BUPIVACAINE-INDUCED IMPAIRMENT OF VENTRICULAR CONDUCTION IN PENTOBARBITAL-ANESTHETIZED DOGS

Possible mechanisms of the ability of clonidine to correct bupivacaine -induced ventricular electrophysiologic impairment were evaluated in a n electrophysiologic model on closed-chest dogs. Nine groups (n = 6) o f pentobarbital-anesthetized dogs were given atropine, 0.2 mg/kg intra venously (IV), and bupivacaine, 4 mg/kg IV, over a 10-s period. Group 1 was then given only saline solution. Group 2 was given clonidine, 0. 01 mg/kg IV, over a 1-min period. Group 3 was given clonidine followed by IV administration of yohimbine, 1 mg/kg, an alpha2-antagonist. Gro up 4 was given carbachol, 1 mg/kg IV, a long-lasting cholinergic agoni st, over a 1-min period. Group 5 was given electrical stimulation of t he left vagus nerve. Group 6 was given physostigmine, 0.1 mg/kg IV, kn own to inhibit cholinesterase degradation, 5 min before bupivacaine ad ministration, and Group 7 received a combination of physostigmine pret reatment and electrical vagal stimulation. Group 8 was given physostig mine, 0.1 mg/kg IV, and pancuronium bromide, 1 mg/kg IV, known to inhi bit nicotinic receptors, 5 min before bupivacaine administration. Then electrical stimulation of the left vagus nerve was performed. Group 9 was given nicotine, 0.1 mg/kg IV, 1 min after bupivacaine injection o ver 1 min. Bupivacaine induced bradycardia, markedly increased the His -Purkinje conduction time (HV interval) and QRS duration. Bupivacaine decreased the peak of first derivative of left ventricle pressure (LVd P/dt(max)) and increased left ventricular end-diastolic pressure (LVED P). Clonidine improved QRS duration and HV interval. Yohimbine did not modify the effects of clonidine. QRS duration and HV interval were si gnificantly improved in Groups 4-7. In Group 8, pancuronium pretreatme nt inhibited the beneficial effects of the combination of physostigmin e pretreatment and electrical vagal stimulation. In contrast, in Group 9, like clonidine, nicotine improved QRS duration and HV interval. Th ree other groups of anesthetized dogs (n = 6) were then studied. All d ogs were given hexamethonium, 10 mg/kg IV. Then, Group 10 was given on ly saline solution; Group 11 was given bupivacaine, 4 mg/kg, and Group 12 was given bupivacaine and nicotine as in Group 9. In Group 11, bup ivacaine induced its usual alterations. In contrast, nicotine did not modify the cardiotoxic profile of bupivacaine after hexamethonium pret reatment. We conclude that the beneficial effect of clonidine on the v ariables of ventricular conduction altered by bupivacaine 1) is not me diated by central alpha2-activation, 2) is mediated by the activation of parasympathetic pathways, and 3) is indirect and not mediated by ac etylcholine release but is mediated by the activation of parasympathet ic ganglionic nicotinic receptors. This activation might induce the re lease of one or several neuropeptides which improve the variables of v entricular conduction.