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Remote preconditioning reduces ischemic injury in the explanted heart by a K_ATP channel-dependent mechanism

¹Department of Cardiology, Skejby Hospital, Aarhus University Hospital, Aarhus, Denmark; ²University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom; and ³Hospital for Sick Children, Toronto, Ontario, Canada

Submitted 4 March 2004 ; accepted in final form 15 October 2004

Local and remote ischemic preconditioning (IPC) reduce ischemia-reperfusion (I/R) injury and preserve cardiac function. In this study, we tested the hypothesis that remote preconditioning is memorized by the explanted heart and yields protection from subsequent I/R injury and that the underlying mechanism involves sarcolemmal and mitochondrial ATP-sensitive K⁺ (K_ATP) channels. Male Wistar rats (300–350 g) were randomized to a control (n = 10), a remote IPC (n = 10), and a local IPC group (n = 10). Remote IPC was induced by four cycles of 5 min of limb ischemia, followed by 5 min of reperfusion. Local IPC was induced by four cycles of 2 min of regional myocardial ischemia, followed by 3 min of reperfusion. The heart was excised within 5 min after the final cycle of preconditioning, mounted in a perfused Langendorff preparation for 40 min of stabilization, and subjected to 45 min of sustained ischemia by occluding the left coronary artery and 120 min of reperfusion. I/R injury was assessed as infarct size by triphenyltetrazolium staining. The influence of sarcolemmal and mitochondrial K_ATP channels on remote preconditioning was assessed by the addition of glibenclamide (10 µM, a nonselective K_ATP blocker), 5-hydroxydecanoic acid (5-HD; 100 µM, a mitochondrial K_ATP blocker), and HMR-1098 (30 µM, a sarcolemmal K_ATP blocker) to the Langendorff preparation before I/R. The role of mitochondrial K_ATP channels as an effector mechanism for memorizing remote preconditioning was further studied by the effect of the specific mitochondrial K_ATP activator diaxozide (10 mg/kg) on myocardial infarct size. Remote preconditioning reduced I/R injury in the explanted heart (0.17 ± 0.03 vs. 0.39 ± 0.05, P < 0.05) and improved left ventricular function during reperfusion compared with control (P < 0.05). Similar effects were obtained with diazoxide. Remote preconditioning was abolished by the addition of 5-HD and glibenclamide but not by HMR-1098. In conclusion, the protective effect of remote preconditioning is memorized in the explanted heart by a mechanism that involves mitochondrial K_ATP channels.

ischemia; transplantation; infarction; ion channels; reperfusion

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