Causes of differential cardiovascular sensitivity to cocaine. II: Sympathetic, metabolic and cardiac effects.

Cocaine elicits a decrease in cardiac output only in a subset of rats; this reduction is mitigated by prazosin, nifedipine, verapamil or pentolinium and exacerbated by propranolol. In the present study, we examined other correlates or causes of differential responsiveness, including differences in cocaine metabolism, sympathetic nerve responses, catecholamine sensitivity and direct cardiac actions. Arterial pressure and heart rate responses to cocaine (5 mg/kg i.v.) were similar in all rats, yet cardiac output responses, as determined by pulsed Doppler flowmetry, varied widely. Cocaine elicited a mean maximal decrease of more than 15% in 17 rats designated responders, whereas the remaining rats (n = 19) were classified as nonresponders. Maximal heart rate responses to phenylephrine- and nitroprusside-induced pressor and depressor stimuli were greater in responders than in nonresponders. Phenylephrine also elicited significantly greater decreases in cardiac output and smaller increases in stroke volume in responders. After we determined the responses to cocaine in conscious rats, animals were anesthetized with alpha-chloralose for renal nerve recording. Several rats (14 of 21 tested) demonstrated an initial brief (2-12 sec) increase in sympathetic activity, whereas all rats subsequently had a delayed sympathoinhibition. Responders were more likely to have sympathoexcitation compared with nonresponders and had an enhanced initial pressor response and a smaller decrease in heart rate. There were no differences in plasma or cerebrospinal fluid levels of cocaine or its metabolites, benzoylecgonine and ecgonine methyl ester. Intravenous benzoylecgonine elicited a pressor response and bradycardia in conscious rats. Finally, there were no differences in contractile, electrocardiographic or coronary vascular responses to cocaine in isolated, perfused hearts from responders and nonresponders. These results suggest that the differential cardiovascular responsiveness to cocaine in rats is mediated, at least in part, by central sympathoexcitation and not by differences in cocaine metabolism or in direct cardiac responsiveness to cocaine.