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Eur J Cardiothorac Surg 2006;30:256-262
© 2006 Elsevier Science NL

Contractile recovery of heart muscle after hypothermic hypoxia is improved by nicorandil via mitochondrial K_ATP channels

^a Department of Cardiothoracic and Vascular Surgery, University Hospital North Norway, P.O. Box 102, N-9038 Tromsø, Norway
^b Department of Medical Physiology, Faculty of Medicine, University of Tromsø, Norway

Received 28 December 2005; received in revised form 21 April 2006; accepted 26 April 2006.

^_* Corresponding author. Tel.: +47 776 26000; fax: +47 776 28298. (Email: tor.steensrud{at}unn.no).

Background: The ATP-sensitive potassium channel (K_ATP) opener nicorandil used instead of potassium in hypothermic cardioplegia significantly improves preservation of cardiac function and energetics in the in situ heart preparation. The present study, therefore, examines the effect of nicorandil at different temperatures and the role of sarcolemmal and mitochondrial K_ATP channels under ex vivo conditions using contractile force (CF) and action potential duration (APD) as end points. Methods: Guinea-pig papillary muscles at 37, 27, or 22 °C (1 Hz) were exposed to nicorandil 0.2–1.1 mM. The contributions of K_ATP channel subtypes in cardioprotection were examined using mitochondrial (mito) (0.1 mM) or non-selective (1.0 mM) concentrations of nicorandil, mito K_ATP blocker 5-hydroxyl decanoate (5HD, 300 µM) or sarcolemmal (sarc) K_ATP blocker HMR1098 (30 µM) before and during 140 min of hypothermic (22 °C) glucose-free hypoxia. Results: Nicorandil >0.5 mM shortened the APD, and this was abolished by hypothermia and HMR1098 but not by 5HD. Nicorandil in both tested concentrations preserved contractile force after hypoxia–reoxygenation significantly better than control (73.7 ± 4.4% and 75.8 ± 3.9% vs 40.6 ± 2.6%, n = 6 in each group). Protection was blocked by 5HD but not by HMR1098. 5HD and HMR1098 alone did not change recovery of contractile force compared to control. Conclusion: Shortening of APD and activation of sarc K_ATP by nicorandil were not related to myocardial protection. Thus, the mito K_ATP seems to play a significant role in cardioprotection compared to the sarc K_ATP also when substrate depletion and hypoxia are combined with hypothermia.

Key Words: Hypoxia • Hypothermia • Cardioplegia