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 delta1 receptors, oxygen radicals, and adenosine triphosphate-sensitive potassium (KATP) channels in mediating this effect.


METHODS
Chick cardiomyocytes were studied in a flow-through chamber while pH, flow 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 microM) 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 +/- 6%, n = 6, in controls) and generated oxygen radicals before ischemia (724 +/- 53, n = 8, and 742 +/- 75, n = 8 [P < 0.05], respectively, vs. 384 +/- 42, n = 6, in controls, arbitrary units). The protection of morphine was abolished by naloxone, or the selective delta1-opioid receptor antagonist 7-benzylidenenaltrexone. Reduction in cell death and increase in oxygen radicals with BW373U86 were blocked by the selective mitochondrial KATP channel antagonist 5-hydroxydecanoate or diethyldithiocarbamic acid (1,000 microM), which inhibited conversion of O2- 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.


CONCLUSIONS
Stimulation of delta1-opioid receptors generates oxygen radicals via mitochondrial KATP channels. This signaling pathway attenuates oxidant stress and cell death in cardiomyocytes.
McPherson
B C
BC
Department of Anesthesia and Critical Care, The University of Chicago, Illinois, USA.
Yao
Z
Z
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D003652:Decanoic Acids / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006880:Hydroxy Acids / Q000494:pharmacology; D054086:KATP Channels; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D017465:Receptors, Opioid, delta / Q000819:agonists; D015398:Signal Transduction / Q000187:drug effects*
D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D001597:Benzylidene Compounds; D003652:Decanoic Acids; D005609:Free Radicals; D006880:Hydroxy Acids; D054086:KATP Channels; D009292:Narcotic Antagonists; D009294:Narcotics; D010879:Piperazines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D017465:Receptors, Opioid, delta; C092520:uK-ATP-1 potassium channel; C077358:7-benzylidenenaltrexone; C083877:BW 373U86; D009270:Naloxone; D009271:Naltrexone; C052853:5-hydroxydecanoic acid