Remote preconditioning reduces ischemic injury in the explanted heart by a K_ATP 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 ϩ (KATP) channels. Male Wistar rats (300 -350 g) were randomized to a control (n ϭ 10), a remote IPC (n ϭ 10), and a local IPC group (n ϭ 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 M, a nonselective KATP blocker), 5-hydroxydecanoic acid (5-HD; 100 M, a mitochondrial KATP blocker), and HMR-1098 (30 M, a sarcolemmal KATP blocker) to the Langendorff preparation before I/R. The role of mitochondrial KATP 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 Ϯ 0.03 vs. 0.39 Ϯ 0.05, P Ͻ 0.05) and improved left ventricular function during reperfusion compared with control (P Ͻ 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.

Serum from Patients Undergoing Remote Ischemic Preconditioning Protects Cultured Human Intestinal Cells from Hypoxia-Induced Damage: Involvement of Matrixmetalloproteinase-2 and -9

“…On a cellular basis, RIPC seems to use similar mechanisms to exert protection to the target organs that have already been described for local preconditioning (41)(42)(43). For the heart, Hausenloy and Yellon (25,29,44) postulated that ischemic preconditioning leads to activation of prosurvival Akt and p42/44 pathways, which result in antiapoptotic effects and protect the organ against I/R injury.…”

Comparison of two sulfonylureas with high and low myocardial KATP channel affinity on myocardial infarct size and metabolism in a rat model of type 2 diabetes

“…A bolus of 1,000 IU/kg heparin (Leo Pharma, Copenhagen, Denmark) was given through the femoral vein. The heart was cannulated in situ, mounted in a Langendorff apparatus and perfused retrogradely with KrebsHenseleit solution at a pressure of 80 mmHg as previously described [16,17]. All hearts were subjected to 40 min preischaemic stabilisation.…”

Cardioprotection Techniques: Preconditioning, Postconditioning and Remote Con-ditioning (Basic Science)

“…Remote limb preconditioning of a pig that had received a donor heart was able to reduce myocardial infarct size in the denervated donor heart, providing strong evidence that a humoral mediator was responsible for RIPC protection, although an afferent sensory nerve pathway from the limb cannot be excluded [168]. A similar type of study was conducted by Kristiansen and colleagues [169] who demonstrated that hearts excised from a rat that had been remote limb preconditioned experienced a smaller infarct size, when subjected to IRI. Other studies have investigated whether endogenous substances such as adenosine [170], bradykinin [171], opioids [172], CGRP [173], and endocannabinoids [174], are released from the remote organ during the preconditioning ischemia and are carried to the heart in the blood stream where they then activate intracellular pathways of cardioprotection.…”

“…Clearly, further work needs to be undertaken to examine the role cardiac nerves contribute to delayed IPC. In this respect, hearts excised from remote limb preconditioned rats generated smaller infarcts on the Langendorff-apparatus [169], suggesting that cardiac innervation at the time of infarction may not be necessary for cardioprotection, presumably because the heart was already in a preconditioned state.…”