Signal transduction of opioid-induced cardioprotection in ischemia-reperfusion

Background: Morphine reduces myocardial ischemia-reperfusion injury in vivo and in vitro. The authors tried to determine the role of opioid delta (1) receptors, oxygen radicals, and adenosine triphosphate-sensitive potassium (K-ATP) channels in mediating this effect. Methods: Chick cardiomyocytes were studied in a flow-through chamber while pH, now rate, oxygen, and carbon dioxide tension were controlled. Cell viability was quantified by nuclear stain propidium iodide, and oxygen radicals were quantified using molecular probe 2 ' ,7 ' -dichlorofluorescin diacetate, Results: Morphine (1 muM or the selective delta -opioid receptor agonist BW373U86 (10 pM) given for 10 min before 1 h of ischemia and 3 h of reoxygenation reduced cell death (31 +/- 5%, n = 6, and 28 +/- 5%, n = 6 [P < 0.05], respectively, 53 <plus/minus> 6%, n = 6, in controls) and generated oxygen radicals before ischemia (724 +/- 53, n = 8, and 742 +/- 75, n = 8 [P < 0,05], respectively, us. 384 +/- 42, n = 6, in controls, arbitrary units). The protection of morphine was abolished by naloxone, or the selective delta (1)-opioid receptor antagonist 7-benzylidenenaltrexone. Reduction in cell death and increase in oxygen radicals with BV373U86 were blocked by the selective mitochondrial K-ATP channel antagonist 5-hydroxydecanoate or diethyldithiocarbamic acid (1000 muM), which inhibited conversion of O-2(-) to H2O2. The increase in oxygen radicals was abolished by the mitochondrial electron transport inhibitor myxothiazol. Reduction in cell death was associated with attenuated oxidant stress at reperfusion. Conclusion: Stimulation of delta (1)-opioid receptors generates oxygen radicals via mitochondrial K-ATP channels. This signaling pathway attenuates oxidant stress and cell death in cardiomyocytes.