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.
Kristiansen et al. (Fri,) studied this question.