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This Article Full Text Full Text (PDF) All Versions of this Article: 292/3/H1470    most recent 00877.2006v1 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 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 Web of Science (12) Citing Articles via Google Scholar Google Scholar Articles by Pasdois, P. Articles by Garlid, K. D. Search for Related Content PubMed PubMed Citation Articles by Pasdois, P. Articles by Garlid, K. D.

Ouabain protects rat hearts against ischemia-reperfusion injury via pathway involving src kinase, mitoK_ATP, and ROS

¹Institut National de la Santé et de la Recherche Médicale U441, University Victor Segalen-Bordeaux 2, University Hospital of Bordeaux, Bordeaux, France; ²Department of Biology, Portland State University, Portland, Oregon; and ³Department of Physiology, Pharmacology, Metabolism, and Cardiovascular Sciences, Medical University of Ohio, Toledo, Ohio

Submitted 15 August 2006 ; accepted in final form 1 November 2006

We showed recently that mitochondrial ATP-dependent K⁺ channel (mitoK_ATP) opening is required for the inotropic response to ouabain. Because mitoK_ATP opening is also required for most forms of cardioprotection, we investigated whether exposure to ouabain was cardioprotective. We also began to map the signaling pathways linking ouabain binding to Na⁺-K⁺-ATPase with the opening of mitoK_ATP. In Langendorff-perfused rat hearts, 10–80 µM ouabain given before the onset of ischemia resulted in cardioprotection against ischemia-reperfusion injury, as documented by an improved recovery of contractile function and a reduction of infarct size. In skinned cardiac fibers, a ouabain-induced protection of mitochondrial outer membrane integrity, adenine nucleotide compartmentation, and energy transfer efficiency was evidenced by a decreased release of cytochrome c and preserved half-saturation constant of respiration for ADP and adenine nucleotide translocase-mitochondrial creatine kinase coupling, respectively. Ouabain-induced positive inotropy was dose dependent over the range studied, whereas ouabain-induced cardioprotection was maximal at the lowest dose tested. Compared with bradykinin (BK)-induced preconditioning, ouabain was equally efficient. However, the two ligands clearly diverge in the intracellular steps leading to mitoK_ATP opening from their respective receptors. Thus BK-induced cardioprotection was blocked by inhibitors of cGMP-dependent protein kinase (PKG) or guanylyl cyclase (GC), whereas ouabain-induced protection was not blocked by either agent. Interestingly, however, ouabain-induced inotropy appears to require PKG and GC. Thus 5-hydroxydecanoate (a selective mitoK_ATP inhibitor), N-(2-mercaptopropionyl)glycine (MPG; a reactive oxygen species scavenger), ODQ (a GC inhibitor), PP2 (a src kinase inhibitor), and KT-5823 (a PKG inhibitor) abolished preconditioning by BK and blocked the inotropic response to ouabain. However, only PP2, 5-HD, and MPG blocked ouabain-induced cardioprotection.

Na⁺-K⁺-ATPase; inotropy; bradykinin; signaling pathway; reactive oxygen species

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