Role of cholinergic receptors and cholinesterase activity in hemodynamic responses to cocaine in conscious rats

It has been suggested that toxicity to cocaine is related to the relative r ate of cocaine metabolism by cholinesterases and to activation of cholinerg ic receptors either directly or by reflex mechanisms. We examined these pos sibilities by altering cholinesterase activity and blocking cholinergic rec eptors in rats prone or resistant to cocaine-induced cardiovascular toxicit y. Rats were instrumented with a pulsed Doppler flow probe on the ascending aorta for measurement of cardiac output and cannulated for arterial pressu re and heart rate determination. In conscious rats, cocaine (5 mg/kg iv) el icited presser responses and a delayed bradycardia but cardiac output and s ystemic vascular resistance responses varied greatly between rats. Pretreat ment with the nonspecific cholinesterase inhibitors physostigmine (0.1-0.2 mg/kg) or neostigmine (0.1 mg/kg) reduced the presser response by diminishi ng the increase in systemic vascular resistance. In contrast, inhibition of cocaine metabolism with the selective plasma cholinesterase inhibitor tetr aisopropyl pyrophosphoramide (0.5 mg/kg) or increasing cholinesterase activ ity with human butyryl cholinesterase (9.9 mg/kg iv) did not alter hemodyna mic responses to cocaine. Administration of atropine methyl bromide (0.5-1 mg/kg iv) alone or with physostigmine mine to prevent the cholinomimetic ef fects of physostigmine reduced the cocaine-induced decrease in cardiac outp ut noted in some animals. These data suggest that the cocaine-induced decre ase in cardiac output observed in some rats is, at least in part, dependent on activation of muscarinic receptors. In addition, the rate of cocaine me tabolism is not critical for the initial hemodynamic responses to cocaine i n conscious rats.