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(Circulation. 1999;100:II-345.)
© 1999 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Preconditioning by Mitochondrial ATP-Sensitive Potassium Channel Openers

An Effective Approach for Improving the Preservation of Heart Transplants

Egidijus Kevelaitis, MD, PhD; Abdeslam Oubénaïssa, MD, PhD; Jacqueline Peynet, MD; Christian Mouas; Philippe Menasché, MD, PhD

From the Departments of Cardiovascular Surgery (P.M.), Biochemistry (J.P.), and INSERM U-127 (A.O., C.M.), Hôpital Lariboisière, Paris, France, and Department of Physiology (E.K.), Kaunas Medical University, Kaunas, Lithuania.

Correspondence to Philippe Menasché, MD, PhD, Department of Cardiovascular Surgery, Hôpital Lariboisière, 2, Rue Ambroise Paré, 75475 Paris 10, France.

Background—Recent studies have implicated mitochondrial ATP-sensitive potassium (K_ATP) channels in the cardioprotective effects of ischemic preconditioning. The present study used a model of prolonged cold heart storage to assess whether the mitochondrial K_ATP opener diazoxide could reproduce the protection conferred by ischemic preconditioning.

Methods and Results—Fifty-four isolated rat hearts were arrested with and stored in Celsior at 4°C for 10 hours before a 2-hour reperfusion. They were divided into 5 groups. Group 1 hearts served as controls. In group 2, hearts were preconditioned by two 5-minute episodes of global ischemia, each separated by 5 minutes of reperfusion before arrest. In group 3, hearts received a 15-minute infusion of the mitochondrial K_ATP opener diazoxide (30 µmol/L) followed by 5 minutes of washout before arrest. In groups 4 and 5, hearts underwent a protocol similar to that used in groups 2 and 3, respectively, except that the preconditioning was preceded by a 10-minute infusion of the mitochondrial K_ATP blocker 5-hydroxydecanoate (5-HD, 100 µmol/L). Both ischemic and diazoxide preconditioning provided a similar degree of cardioprotection demonstrated by a significantly better preservation of left ventricular compliance, reduced leakage of creatine kinase, and smaller degree of myocardial edema compared with control hearts. These beneficial effects were abolished by 5-HD pretreatment. Postischemic left ventricular contractility and endothelium-dependent coronary response to 5-hydroxytryptamine and acetylcholine were not different among groups. However, the endothelium-independent vasodilatory postischemic response to papaverine was better preserved after ischemic and diazoxide preconditioning than in the other groups.

Conclusions—These data support the concept that the cardioprotective effects of ischemic preconditioning can be duplicated by a mitochondrial K_ATP opener and suggest that activation of these channels could be an effective means of improving the preservation of globally ischemic cold-stored hearts, as occurs during cardiac transplantation.

Key Words: ischemia • reperfusion • diastole • systole • vasodilation