HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 290/2/H830    most recent 00799.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Przyklenk, K. Articles by Whittaker, P. Search for Related Content PubMed PubMed Citation Articles by Przyklenk, K. Articles by Whittaker, P.

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

This article has been cited by other articles:

				K. Przyklenk, M. Maynard, and P. Whittaker First molecular evidence that inositol trisphosphate signaling contributes to infarct size reduction with preconditioning Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H2008 - H2012. [Abstract] [Full Text] [PDF]

				A. A. Lanzafame, L. Turnbull, F. Amiramahdi, J. F. Arthur, H. Huynh, and E. A. Woodcock Inositol phospholipids localized to caveolae in rat heart are regulated by {alpha}1-adrenergic receptors and by ischemia-reperfusion Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H2059 - H2065. [Abstract] [Full Text] [PDF]