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Am J Physiol Heart Circ Physiol 285: H2463-H2470, 2003. First published July 17, 2003; doi:10.1152/ajpheart.00341.2003
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Sustained exogenous administration of Met5-enkephalin protects against infarction in vivo

Koh Kuzume,1 Roger A. Wolff,2 Kazuhiko Amakawa,4 Kazuyo Kuzume,1 and Donna M. Van Winkle1,2,3

1Department of Anesthesiology, Oregon Health and Sciences University, and Departments of 2Research and 3Anesthesiology Services, Veterans Affairs Medical Center, Portland, Oregon 97201; and 4Department of Anesthesiology and Resuscitology, Ehime University School of Medicine, Ehime, Japan 791-0295

Submitted 17 April 2003 ; accepted in final form 10 July 2003

The opioid antagonist naloxone abolishes infarct limitation by myocardial ischemic preconditioning, suggesting that one or more endogenous opioid peptides can mediate cardiac protection against ischemic damage. We tested the hypothesis that the naturally occurring opioid peptide Met5-enkephalin (ME) modulates myocardial infarct size in vivo. Experiments were conducted in barbiturate-anesthetized open-chest rabbits subjected to regional myocardial ischemia-reperfusion. ME was administered via osmotic minipump for 24 h. Infarct size was assessed with tetrazolium and is expressed as a percentage of the area at risk. Exogenous ME reduced the amount of the risk zone infarcted by ~60% compared with saline-treated controls. ME-induced protection was sensitive to opioid receptor blockade with naloxone [NAL 50 ± 2% vs. ME + NAL 39 ± 3%, P = not significant (NS)] and also to blockade of sarcolemmal and mitochondrial ATP-sensitive K+ (KATP) channels [5-hydroxydecanoate (5-HD) 33 ± 3% vs. ME + 5-HD 43 ± 8%, P = NS; and HMR-1098 60 ± 3% vs. ME + HMR-1098 54 ± 7%, P = NS]. We conclude that ME limits ischemic injury in vivo by an opioid receptor-mediated mechanism that involves both sarcolemmal and mitochondrial KATP channels.

ischemia; infarction; ischemic preconditioning; myocardial peptides; opioid


Address for reprint requests and other correspondence: D. M. Van Winkle, Research Physiologist, Anesthesiology Service, P3ANES, DVA Medical Center, 3710 SW US Veterans Hospital Rd., Portland, OR 97201 (E-mail: Donna.Vanwinkle{at}med.va.gov).




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