Differential effects of cocaine and cocaethylene on intracellular Ca2+ and myocardial contraction in cardiac myocytes.

1. Isolated cardiac myocytes of the ferret were used to investigate the influence of cocaine and cocaethylene on the intracellular Ca2+ transient indicated by the indo-1 405/480 nm ratio signal, and peak cell shortening. 2. Both cocaine and cocaethylene produced significant decreases in peak intracellular Ca2+ and peak cell shortening in a dose-dependent manner. Of interest, (1) the minimally effective dose of cocaethylene was ten fold lower (10(-8)M versus 10(-7)M) than that of cocaine; (2) the log EC50 of cocaethylene was -5.99 +/- 0.13 (1.0 x 10(-6) M), which was about ten fold lower than that of cocaine (-5.02 +/- 0.11, 9.6 x 10(-6) M); and (3) 1 x 10(-4)M cocaethylene decreased the contraction amplitude by 71 +/- 7%, while the same concentration of cocaine decreased the amplitude only by 55 +/- 5%, indicating that cocaethylene is more potent than cocaine. 3. The negative inotropic effects of either cocaine or cocaethylene could be overcome by noradrenaline (approximately 5 microM) or calcium. 4. In contrast to cocaine, cocaethylene shifted the peak [Ca2+]i-peak shortening relationship downward, indicating that cocaethylene decreased myofilament Ca(2+)-responsiveness. 5. These data indicate that both cocaine and cocaethylene act directly on cardiac myocytes to produce a negative inotropic effect that is due to decreased Ca2+ availability. In contrast to cocaine, cocaethylene produces more potent inhibition by an additional action to decrease myofilament Ca(2+)-responsiveness.