Pasdois 2007 Am J Physiol Heart Circ Physiol

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Pasdois P, Quinlan CL, Rissa A, Tariosse L, Vinassa B, Costa AD, Pierre SV, Dos Santos P, Garlid KD (2007) Ouabain protects rat hearts against ischemia-reperfusion injury via pathway involving src kinase, mitoKATP, and ROS. Am J Physiol Heart Circ Physiol 292:H1470-8.

» PMID: 17098831 Open Access

Pasdois P, Quinlan CL, Rissa A, Tariosse L, Vinassa B, Costa AD, Pierre SV, Dos Santos P, Garlid KD (2007) Am J Physiol Heart Circ Physiol

Abstract: We showed recently that mitochondrial ATP-dependent K+ channel (mitoKATP) opening is required for the inotropic response to ouabain. Because mitoKATP 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 mitoKATP. 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 mitoKATP 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 mitoKATP 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. Keywords: Na+-K+-ATPase, Inotropy, Bradykinin, Signaling pathway, Reactive oxygen species

O2k-Network Lab: FR Pessac Diolez P

Labels: MiParea: Respiration, Pharmacology;toxicology 

Stress:Ischemia-reperfusion, Oxidative stress;RONS  Organism: Rat  Tissue;cell: Heart  Preparation: Permeabilized tissue  Enzyme: Complex IV;cytochrome c oxidase, Inner mt-membrane transporter  Regulation: Cyt c, Inhibitor, Ion;substrate transport 

HRR: Oxygraph-2k