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.
Qiu
Z
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Harvard-Thorndike Laboratory, Beth Israel Hospital, Harvard Medical School, Boston, MA.
Morgan
J P
JP
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D003042:Cocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005289:Ferrets; D005456:Fluorescent Dyes; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology
D005456:Fluorescent Dyes; D007211:Indoles; D014179:Neurotransmitter Uptake Inhibitors; C066444:cocaethylene; D003042:Cocaine; C048960:indo-1; D002118:Calcium; D009638:Norepinephrine