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1 Department of Cardiology, Aarhus University Hospital, Skejby Hospital, Aarhus, Denmark
2 Department of Cardiology, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
3 Department of Cardiology, Hospital for Sick Children, Toronto, Canada
* To whom correspondence should be addressed. E-mail: sbk{at}iekf.au.dk.
Background- Local and remote ischemic preconditioning (IPC) reduce ischemia-reperfusion (IR) 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 IR injury and that the underlying mechanism involve sarcolemmal and mitochondrial KATP channels. Methods- 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 4 cycles of 5 minutes of limb ischemia followed by 5 minutes of reperfusion. Local IPC was induced by 4 cycles of 2 minutes of regional myocardial ischemia followed by 3 minutes of reperfusion. The heart was excised within 5 minutes after the final cycle of preconditioning, mounted in a perfused Langendorff preparation for 40 minutes of stabilization and subjected to 45 minutes of sustained ischemia by occluding the left coronary artery and 120 minutes of reperfusion. IR injury was assessed as infarct size by a triphenyltetrazolium staining. The influence of sarcolemmal and mitochondrial KATP channels on remote preconditioning was assessed by addition of glibenclamide (10 µM)(a non selective KATP blocker), 5-hydroxydecanoic acid (5-HD)(100 µM)(a mitochondrial KATP blocker) and HMR 1098 (30µM) (a sarcolemmal KATP blocker) to the Langendorff preparation prior to IR. The role mitochondrial KATP-channels as an effector mechanism for memorizing remote preconditioning was further studied by the effect of the specific mitochondrial KATP activator diaxozide (10 mg/kg) on myocardial infarct size. Result-Remote preconditioning reduced IR-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 addition of 5-HD and glibenclamide but not by HMR 1098. Conclusion- The protective effect of remote preconditioning is memorized in the explanted heart by a mechanism that involves mitochondrial KATP channels.
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