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(Circulation Research. 1999;84:1396-1400.)
© 1999 American Heart Association, Inc.

Original Contribution

Direct Preconditioning of Cardiac Myocytes via Opioid Receptors and K_ATP Channels

Bruce T. Liang, Garrett J. Gross

From the Department of Medicine (B.T.L.), Cardiovascular Division, University of Pennsylvania Medical Center, Philadelphia, and the Department of Pharmacology and Toxicology (G.J.G.), Medical College of Wisconsin, Milwaukee.

Correspondence to Bruce T. Liang, MD, 504 Johnson Pavilion, University of Pennsylvania Medical Center, 3610 Hamilton Walk, Philadelphia, PA 19104. E-mail liangb{at}mail.med.upenn.edu

Abstract—Previous studies demonstrated that opioid receptor activation mimics the cardioprotective effect of ischemic preconditioning via K_ATP channels in the intact heart. However, it is unknown whether this beneficial effect is exerted at the level of the cardiac myocyte or coronary vasculature or is mediated via the sarcolemmal or the mitochondrial K_ATP channel. Thus, the purpose of the present study was to investigate whether opioid receptor stimulation could mimic the cardioprotective effect of preconditioning in a cardiac myocyte model of simulated ischemia. Cardiac ventricular myocytes cultured from chick embryos 14 days in ovo were used as an in vitro model for ischemic preconditioning. A 5-minute exposure of the myocytes to the opioid receptor agonist morphine protected the myocytes during a subsequent 90-minute period of simulated ischemia, which was manifested as a pronounced reduction in the percentage of cardiac cells killed and the amount of creatine kinase released during ischemia. The preconditioning-like effect of morphine was concentration-dependent, reached a maximal effect at 1 µmol/L, and was reversed by naloxone (0.1 to 10 µmol/L). When K_ATP channel antagonists, such as glibenclamide, or the mitochondrial selective inhibitor 5-hydroxydecanoic acid were present during preexposure to morphine, they abolished the protective effect of morphine. Thus, cardiac myocytes express functional opioid receptors, and their activation mimics the cardioprotective effect of ischemic preconditioning. These results provide direct evidence that the preconditioning-like effect of morphine in the intact heart can be exerted at the level of cardiac myocytes and is most likely the result of mitochondrial K_ATP channel activation.

Key Words: myocyte • cardioprotection • receptor • morphine • channel

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