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 viab ility was quantified by nuclear stain propidium iodide, and oxygen radicals were quantified using molecular probe 2 ' ,7 ' -dichlorofluorescin diaceta te, Results: Morphine (1 muM or the selective delta -opioid receptor agonist BW 373U86 (10 pM) given for 10 min before 1 h of ischemia and 3 h of reoxygena tion 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). Th e protection of morphine was abolished by naloxone, or the selective delta (1)-opioid receptor antagonist 7-benzylidenenaltrexone. Reduction in cell d eath and increase in oxygen radicals with BV373U86 were blocked by the sele ctive mitochondrial K-ATP channel antagonist 5-hydroxydecanoate or diethyld ithiocarbamic acid (1000 muM), which inhibited conversion of O-2(-) to H2O2 . The increase in oxygen radicals was abolished by the mitochondrial electr on transport inhibitor myxothiazol. Reduction in cell death was associated with attenuated oxidant stress at reperfusion. Conclusion: Stimulation of delta (1)-opioid receptors generates oxygen radi cals via mitochondrial K-ATP channels. This signaling pathway attenuates ox idant stress and cell death in cardiomyocytes.