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Morphine Mimics Preconditioning via Free Radical Signals and Mitochondrial K ATP Channels in Myocytes

2001; Lippincott Williams & Wilkins; Volume: 103; Issue: 2 Linguagem: Inglês

10.1161/01.cir.103.2.290

1524-4539

Bradley C. McPherson, Zhenhai Yao,

Anesthesia and Neurotoxicity Research

Background —We tried to determine whether morphine mimics preconditioning (PC) to reduce cell death in cultured cardiomyocytes and whether opioid δ 1 receptors, free radicals, and K ATP channels mediate this effect. Methods and Results —Chick embryonic ventricular myocytes were studied in a flow-through chamber while flow rate, pH, and O 2 and CO 2 tension were controlled. Cardiomyocyte viability was quantified with propidium iodide (5 μmol/L), and production of free radicals was measured with 2′,7′-dichlorofluorescin diacetate. PC with 10 minutes of simulated ischemia before 10 minutes of reoxygenation or morphine (1 μmol/L) or BW373U86 (10 pmol/L) infusion for 10 minutes followed by a 10-minute drug-free period before 1 hour of ischemia and 3 hours of reoxygenation reduced cell death to the same extent (* P <0.05) (PC, 20±1%, n=7*; morphine, 32±4%, n=8*; BW373U86, 21±6%; controls, 52±5%, n=8). Like PC, morphine and BW373U86 increased free radical production 2-fold before ischemia (0.35±0.10, n=6*; 0.41±0.08, n=4* versus controls, 0.15±0.05, n=8, arbitrary units). Protection and increased free radical signals during morphine infusion were abolished with either the thiol reductant 2-mercaptopropionyl glycine (400 μmol/L), an antioxidant; naloxone (10 μmol/L), a nonselective morphine receptor antagonist; BNTX (0.1 μmol/L), a selective opioid δ 1 receptor antagonist; or 5-hydroxydecanoate (100 μmol/L), a selective mitochondrial K ATP channel antagonist. Conclusions —These results suggest that direct stimulation of cardiocyte opioid δ 1 receptors leads to activation of mitochondrial K ATP channels. The resultant increase of intracellular free radical signals may be an important component of the signaling pathways by which morphine mimics preconditioning in cardiomyocytes.