title: Remote preconditioning reduces ischemic injury in the explanted heart by a KATP channel-dependent mechanism.
abstract: 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 microM, a nonselective K(ATP) blocker), 5-hydroxydecanoic acid (5-HD; 100 microM, a mitochondrial K(ATP) blocker), and HMR-1098 (30 microM, 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.
authors.affiliation: Department of Cardiology, Skejby Hospital, Aarhus University Hospital, Aarhus, Denmark. sbk@iekf.au.dk <sbk@iekf.au.dk>
authors.forename: Steen B
authors.initials: SB
authors.lastname: Kristiansen
authors.forename: Ole
authors.initials: O
authors.lastname: Henning
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Kharbanda
authors.forename: Jens Erik
authors.initials: JE
authors.lastname: Nielsen-Kudsk
authors.forename: Michael Rahbek
authors.initials: MR
authors.lastname: Schmidt
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Redington
authors.forename: Torsten Toftegaard
authors.initials: TT
authors.lastname: Nielsen
authors.forename: Hans Erik
authors.initials: HE
authors.lastname: Bøtker
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003326:Coronary Circulation / Q000502:physiology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D016277:Ventricular Function, Left / Q000502:physiology; D017725:Ventricular Pressure / Q000502:physiology
chemical_list: D015221:Potassium Channels; D000255:Adenosine Triphosphate