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Chronic preconditioning: a novel approach for cardiac protection

Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio

Submitted 23 October 2006 ; accepted in final form 2 January 2007

Ischemic preconditioning is the most powerful protective mechanism known against lethal ischemia. Unfortunately, the protection lasts for only a few hours. Here we tested the hypothesis that the heart can be kept in a preconditioned state for constant protection against ischemia. In this study we chose BMS-191095 (BMS), a highly selective opener of mitochondrial ATP-sensitive K⁺ (mitoK_ATP) channels. BMS (1 mg/kg ip) was administered to rats every 24 h until 96 h. In other groups, BMS plus wortmannin (WTN, 15 µg/kg ip), an inhibitor of the phosphatidylinositol 3-kinase (PI3-K), or BMS plus 5-hydroxydecanoic acid (5-HD, 5 mg/kg ip), an inhibitor of mitoK_ATP, or BMS plus N-nitro-L-arginine methyl ester (L-NAME) (30 µg/kg ip), an inhibitor of nitric oxide (NO) synthase, were administered to rats. Rats were then subjected to 30-min left anterior descending coronary artery occlusion and 120-min reperfusion. Cardiac function, infarct size, pathological changes, and apoptosis were assessed at the end of treatments. Saline-treated hearts displayed marked contractile dysfunction and underwent pathological changes. BMS-treated rats showed significant improvement in cardiac function, and infarct size was significantly reduced in BMS-treated hearts. However, protection by BMS was abolished by 5-HD, WTN, or L-NAME. These data demonstrate that hearts can be chronically preconditioned and retain their ability to remain resistant against lethal ischemia and that this protection is mediated by activation of mitoK_ATP via NO and PI3-K/Akt signaling pathways.

mitochondrial ATP-sensitive K⁺ channels; BMS-191095; heart function

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