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Morphine mimics the antiapoptotic effect of preconditioning via an Ins(1,4,5)P₃ signaling pathway in rat ventricular myocytes

Laboratoire de Génomique Fonctionnelle, Centre National de la Recherche Scientifique, Montpellier Cedex 5, France

Submitted 15 September 2003 ; accepted in final form 18 August 2004

Morphine has cardioprotective effects against ischemic-reperfusion injuries. This study investigates whether morphine could mimic the antiapoptotic effect of preconditioning using a model of cultured neonatal rat cardiomyocytes subjected to metabolic inhibition (MI). To quantify MI-induced apoptosis, DNA fragmentation and mitochondrial cytochrome c release levels were measured by ELISA. MI-dependent DNA fragmentation was prevented by both Z-VAD-fmk (20 µM), a pan-caspase inhibitor, and cyclosporine A (CsA; 5 µM), a mitochondrial pore transition blocker, added during MI (36% and 54% decrease, respectively). MI-dependent cytochrome c release was not blocked by Z-VAD-fmk but was decreased (38%) by CsA during MI. Metabolic preconditioning (MIP) and preconditioning with morphine (1 µM) were also assessed. MI-dependent DNA fragmentation and cytochrome c release were prevented by MIP (40% and 45% decrease, respectively) and morphine (34% and 45%, respectively). The antiapoptotic effect of morphine was abolished by naloxone (10 nM), a nonselective opioid receptor antagonist, or xestospongin C (XeC, 400 nM), an inhibitor of inositol (1,4,5)-trisphosphate [Ins(1,4,5)P₃]-mediated Ca²⁺ release. Ca²⁺ preconditioning, induced by increasing extracellular Ca²⁺ from 1.8 to 3.3 mM, mimicked the antiapoptotic effect of morphine on DNA fragmentation (24% decrease) and cytochrome c release (57% decrease). This effect mediated by extracellular Ca²⁺ was also abolished by XeC. Measurements of intracellular Ca²⁺ concentration using fura-2 microspectrofluorimetry showed that morphine induces Ins(1,4,5)P₃-dependent Ca²⁺ transients abolished by 2-aminoethoxydiphenyl borate (2-APB), a cell-permeable Ins(1,4,5)P₃ antagonist. These results suggest that morphine preconditioning prevents simulated ischemia-reperfusion-induced apoptosis via an Ins(1,4,5)P₃ signaling pathway in rat ventricular myocytes.

opioid; cardioprotection; calcium

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