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Nitric oxide-cGMP-protein kinase G signaling pathway induces anoxic preconditioning through activation of ATP-sensitive K⁺ channels in rat hearts

¹Mitochondrial Signaling Laboratory, Department of Physiology and Biophysics, College of Medicine, Cardiovascular and Metabolic Disease Center, Biohealth Products Research Center, Inje University; and ²Department of Pharmaceutical Engineering, Silla University, Busan, Korea

Submitted 21 July 2005 ; accepted in final form 30 November 2005

Nitric oxide (NO) plays an important role in anoxic preconditioning to protect the heart against ischemia-reperfusion injuries. The present work was performed to study better the NO-cGMP-protein kinase G (PKG) signaling pathway in the activation of both sarcolemmal and mitochondrial ATP-sensitive K⁺ (K_ATP) channels during anoxic preconditioning (APC) and final influence on reducing anoxia-reperfusion (A/R)-induced cardiac damage in rat hearts. The upstream regulating elements controlling NO-cGMP-PKG signal-induced K_ATP channel opening that leads to cardioprotection were investigated. The involvement of both inducible and endothelial NO synthases (iNOS and eNOS) in the progression of this signaling pathway was followed. Final cellular outcomes of ischemia-induced injury after different preconditioning in the form of lactate dehydrogenase release, DNA strand breaks, and malondialdehyde formation as indexes of cell injury and lipid peroxidation, respectively, were investigated. The lactate dehydrogenase and malondialdehyde values decreased in the groups that underwent preconditioning periods with specific mitochondrial K_ATP channels opener diazoxide (100 µM), nonspecific mitochondrial K_ATP channels opener pinacidil (50 µM), S-nitroso-N-acetylpenicillamine (SNAP, 300 µM), or -phenyl-1,N²-etheno-8-bromoguanosine-3',5'-cyclicmonophosphorothioate, Sp-isomer (10 µM) before the A/R period. Preconditioning with SNAP significantly reduced the DNA damage. The effect was blocked by glibenclamide (50 µM), 5-hydroxydecanoate (100 µM), N^G-nitro-L-arginine methyl ester (200 µM), and -phenyl-1,N²-etheno-8-bromoguanosine-3',5'-cyclic monophosphorothioate, Rp-isomer (1 µM). The results suggest iNOS, rather than eNOS, as the major contributing NO synthase during APC treatment. Moreover, the PKG shows priority over NO as the upstream regulator of NO-cGMP-PKG signal-induced K_ATP channel opening that leads to cardioprotection during APC treatment.

guanosine 3',5'-cyclic monophosphate; adenosine 5'-triphosphate; oxidative damage

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