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(Circulation. 2001;103:290.)
© 2001 American Heart Association, Inc.

Basic Science Reports

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

Bradley C. McPherson, BA; Zhenhai Yao, MD, PhD

From the Department of Anesthesia and Critical Care, the University of Chicago, Chicago, Ill.

Background—We tried to determine whether morphine mimics preconditioning (PC) to reduce cell death in cultured cardiomyocytes and whether opioid 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 O₂ and CO₂ 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 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 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.

Key Words: free radicals • ion channels • receptors • preconditioning

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