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Reduction of infarct size with D-myo-inositol trisphosphate: role of PI3-kinase and mitochondrial K_ATP channels

Departments of ¹Emergency Medicine and ²Anesthesiology, University of Massachusetts Medical School, Worcester, Massachusetts

Submitted 27 July 2005 ; accepted in final form 20 September 2005

Prophylactic treatment with D-myo-inositol 1,4,5-trisphosphate hexasodium [D-myo-Ins(1,4,5)P₃], the sodium salt of the endogenous second messenger Ins(1,4,5)P₃, triggers a reduction of infarct size comparable in magnitude to that seen with ischemic preconditioning (PC). However, the mechanisms underlying D-myo-Ins(1,4,5)P₃-induced protection are unknown. Accordingly, our aim was to investigate the role of four archetypal mediators implicated in PC and other cardioprotective strategies (i.e., PKC, PI3-kinase/Akt, and mitochondrial and/or sarcolemmal K_ATP channels) in the infarct-sparing effect of D-myo-Ins(1,4,5)P₃. Fifteen groups of isolated buffer-perfused rabbit hearts [5 treated with D-myo-Ins(1,4,5)P₃, 5 treated with PC, and 5 control cohorts] underwent 30 min of coronary artery occlusion and 2 h of reflow. One set of control, D-myo-Ins(1,4,5)P₃, and PC groups received no additional treatment, whereas the remaining sets were infused with chelerythrine, LY-294002, 5-hydroxydecanoate (5-HD), or HMR-1098 [inhibitors of PKC, PI3-kinase, and mitochondrial and sarcolemmal ATP-sensitive K⁺ (K_ATP) channels, respectively]. Infarct size (delineated by tetrazolium staining) was, as expected, significantly reduced in both D-myo-Ins(1,4,5)P₃- and PC-treated hearts versus controls. D-myo-Ins(1,4,5)P₃-induced cardioprotection was blocked by 5-HD but not HMR-1098, thereby implicating the involvement of mitochondrial, but not sarcolemmal, K_ATP channels. Moreover, the benefits of D-myo-Ins(1,4,5)P₃ were abrogated by LY-294002, whereas, in contrast, chelerythrine had no effect. These latter pharmacological data were corroborated by immunoblotting: D-myo-Ins(1,4,5)P₃ evoked a significant increase in expression of phospho-Akt but had no effect on the activation/translocation of the cardioprotective -isoform of PKC. Thus PI3-kinase/Akt signaling and mitochondrial K_ATP channels participate in the reduction of infarct size afforded by prophylactic administration of D-myo-Ins(1,4,5)P₃.

myocardial ischemia; myocardial infarction; signal transduction; preconditioning

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