Mechanism of the systemic, left ventricular, and coronary vascular tolerance to a binge of cocaine in conscious dogs.

BACKGROUND

Prior experimental studies have emphasized the cardiovascular effects of acute, single doses of cocaine. However, cardiovascular complications are most often reported in chronic users, who have been exposed to repetitive doses of cocaine. It remains unclear whether there is tolerance or sensitization to the systemic, left ventricular, and coronary hemodynamic effects of a binge of cocaine.

METHODS AND RESULTS

We studied 11 conscious, chronically instrumented dogs to determine the systemic pressor, inotropic, chronotropic, and coronary vascular resistance responses to cocaine (1 mg/kg IV) administered every 25 minutes for five doses. There was progressive tolerance to the systemic pressor (mean arterial pressure: first dose, +42 +/- 4% from 97 +/- 2 mm Hg; fifth dose, +8 +/- 3% from 116 +/- 7 mm Hg; P < .01) and heart rate (first dose, +45 +/- 8% from 93 +/- 5 bpm; fifth dose, +8 +/- 2% from 109 +/- 9 bpm; P < .01) responses and abolition of the positive inotropic (left ventricular dP/dt: first dose, +19 +/- 4% from 2824 +/- 75 mm Hg/s; fifth dose, -3 +/- 5% from 2531 +/- 436 mm Hg/s; P < .01) and coronary vasoconstrictor (coronary vascular resistance: first dose, +38 +/- 9% from 1.9 mm Hg.mL-1.min-1; fifth dose, -7 +/- 2% from 2.6 +/- 0.2 mm Hg. mL-1.min-1; P < .01) responses to a binge of cocaine despite progressive increases in peak plasma cocaine concentrations. In contrast, both the plasma norepinephrine and epinephrine responses were attenuated with repetitive exposure to cocaine, whereas myocardial alpha and beta-adrenergic responsiveness was maintained.

CONCLUSIONS

Repetitive cocaine administration is associated with the development of early and progressive tolerance to systemic, left ventricular, and coronary vascular effects of cocaine. The mechanism of the tolerance involves neither impaired myocardial nor coronary vascular responsiveness to adrenergic stimulation but, rather, attenuated catecholamine responses to repetitive cocaine administration.