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

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-l 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-M) than that of cocaine; (2) the log EC, of cocaethylene was -5.99 ± 0.13 (1.0 x 10-6M), 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 (5 gM) 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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“…In addition, CE has been shown to block calcium channels in cardiac myocytes, which may partially explain the prolongation of the myocardial refractory period and resultant prolongation of the QTc interval. 32 The present data suggest that CϩE and CE do not significantly increase heart rate and may depress cardiac compensatory chronotropic responses. Cocaine and CE have been shown to decrease depolarization at the sinoatrial node, possibly by depressing the slowly activated current in the phase 4 action potential.…”

“…Cocaine is a potent blocker of fast sodium channels in cardiac myocytes, which has been postulated to be a possible mechanism of cocaine-related dysrhythmias and sudden death. 30,31 Cocaethylene affects the cardiac conduction system and myocytes by blocking sodium channels 32 and is a more potent blocker of sodium channels than cocaine. 30 The substantial acute prolongations of QRS intervals in the present experiments were comparable in dogs receiving cocaine and CϩE, suggesting that after the acute bolus, cocaine-induced sodium channel blockade was the predominant factor.…”

“…Cocaethylene has more negative ionotropic effects on myocytes than cocaine. 32 Both cocaine and CE, by blocking sodium channels, cause significant abnormalities in ventricular depolarization and, by interfering with the normal patterns of ventricular depolarization and repolarization, affect contractility and relaxation. Both cocaine and CE, because of their sodium channelblocking effects, reduce available sodium for Na ϩ / Ca ϩϩ exchange.…”

“…This would result in decreased calcium influx into myocytes during membrane depolarization. 30,32,38 Both may also directly inhibit voltage-sensitive calcium channels in the sarcolemma. 32,38 By all of these mechanisms, cocaine and CE could make less calcium available for loading of the sarcoplasmic reticulum and the contractile apparatus.…”

“…30,32,38 Both may also directly inhibit voltage-sensitive calcium channels in the sarcolemma. 32,38 By all of these mechanisms, cocaine and CE could make less calcium available for loading of the sarcoplasmic reticulum and the contractile apparatus. The negative ionotropic effects of ethanol are well described, and are predominantly due to decreased myofilament responsiveness to Ca ϩϩ and decreased calcium transients into myocardial cells.…”