Cocaine produces apparent myocardial ischemia in some individuals without deleterious effects in others. The authors identified a subset of rats in which cocaine produces a decrease in cardiac output and an increase in cardiomyopathies. In the present study, several potential causes of this differential responsiveness were examined in conscious rats instrumented for cardiac output determination by using pulsed Doppler flowmetry. Although arterial pressure and heart rate responses to cocaine (5 mg/kg i.v.) were similar in all rats, cardiac output responses varied widely. Specifically, in 17 of 36 rats, cocaine elicited a maximum decrease of greater than 15% that was relatively consistent with repeated trials. These rats were designated responders, whereas the remaining rats with little change or an increase in cardiac output were classified as nonresponders. Pentolinium (7.5 mg/kg) or adrenal demedullation reduced the peak cardiac output responses in both groups such that there was no longer a difference between responders and nonresponders. Prazosin (0.1 mg/kg) reduced the cocaine-induced pressor responses in all rats and selectively reduced the decrease in cardiac output in responders. Propranolol (1 mg/kg) reduced the peak pressor response but enhanced the decrease in cardiac output in responders. Neither indomethacin (5 mg/kg) or heparin (300 units) pretreatment altered the cocaine-induced cardiac output or peripheral vascular effects in either responders or nonresponders. Amphetamine (1 mg/kg) elicited smaller pressor responses but still evoked a net decrease in cardiac output in responders.(ABSTRACT TRUNCATED AT 250 WORDS)