Role of cholinergic receptors and cholinesterase activity in hemodynamic responses to cocaine in conscious rats. Knuepfer, Mark M., and Qi Gan. Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, St. Louis, MO, USA 63104
APStracts 5:0345R, 1998.
It has been suggested that toxicity to cocaine is related to the relative rate of cocaine metabolism by cholinesterases and to activation of cholinergic receptors either directly or by reflex mechanisms. We examined these possibilities by altering cholinesterase activity and blocking cholinergic receptors in rats prone or resistant to cocaine-induced cardiovascular toxicity. Rats were instrumented with a pulsed Doppler flowprobe on the ascending aorta for measurement of cardiac output and cannulated for arterial pressure and heart rate determination. In conscious rats, cocaine (5 mg/kg, i.v.) elicited pressor responses and a delayed bradycardia but cardiac output and systemic vascular resistance responses varied greatly between rats. Pretreatment with the nonspecific cholinesterase inhibitors physostigmine (0.1-0.2 mg/kg) or neostigmine (0.1 mg/kg) reduced the pressor response by diminishing the increase in systemic vascular resistance. In contrast, inhibition of cocaine metabolism with the selective plasma cholinesterase inhibitor iso-OMPA (tetraisopropyl pyrophosphamide, 0.5 mg/kg) or increasing cholinesterase activity with human butyrylcholinesterase (9.9 mg/kg, i.v.) did not alter hemodynamic responses to cocaine. Administration of atropine methylbromide (0.5-1 mg/kg, i.v.) alone or with physostigmine to prevent the cholinomimetic effects of physostigmine reduced the cocaine-induced decrease in cardiac output noted in some animals. These data suggest that the cocaine-induced decrease in cardiac output observed in some rats is, at least in part, dependent on activation of muscarinic receptors. In addition, the rate of cocaine metabolism is not critical for the initial hemodynamic responses to cocaine in conscious rats. 

Received 25 March 1998; accepted in final form 31 August 1998.
APS Manuscript Number R186-8.
Article publication pending Am. J. Physiol. (Regulatory Integrative
Comp. Physiology).
ISSN 1080-4757 Copyright 1998 The American Physiological Society.
Published in APStracts on 21 September 1998