Comparison of the effects of cocaine and its metabolites on cardiovascular function in anesthetized rats

Hemodynamic and cardiac-electrophysiologic effects of cocaine and its metabolites were measured in 18 groups (n = 6 each) of anesthetized, artificially ventilated rats during continuous intravenous (i.v.) infusions at three different doses (0.15, 0.45, and 1.5 mg/kg/min). At the highest dose, cocaine decreased blood pressure (BP) and heart rate (HR), while QRS duration, an index of cocaine's local anesthetic effect, was increased. Cocaethylene, a metabolite produced after coadministration of cocaine and ethanol, had effects comparable to those of cocaine. The cocaine metabolite norcocaine produced a decrease in BP at the lower dose that reversed to a small increase at the higher dose. The highest dose of norcocaine clearly decreased HR and increased QRS duration. The increases in QRS duration observed for cocaine, cocaethylene, and norcocaine were reversed by sodium bicarbonate. The cocaine metabolites benzoylecgonine and ecgonine methyl ester increased BP at the higher doses without affecting either HR or QRS duration. These results suggest that the spectrum of effects produced by cocaine are not necessarily mimicked by its metabolites. In particular, accumulation of the persistent, active metabolites benzoylecgonine and ecgonine methyl ester may contribute to delayed-onset, cocaine-related toxicity.