Differential effects of cocaine and cocaethylene on intracellular Ca24+ and myocardial contraction in cardiac myocytes

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Abstract
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 × 10−6 m), which was about ten fold lower than that of cocaine (−5.02 ± 0.11, 9.6 × 10−6 m); and (3) 1 × 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 (∼ 5 μm) or calcium. 4 In contrast to cocaine, cocaethylene shifted the peak [Ca2+]i‐peak shortening relationship downward, indicating that cocaethylene decreased myofilament Ca2+‐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 Ca2+‐responsiveness.

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