Mitochondrial K(ATP) channel as an end effector of cardioprotection during late preconditioning: triggering role of nitric oxide.
Nitric oxide (NO) has been implicated in the "second-window" of ischemic preconditioning (PC). However, the identity of the end effector after initiation of preconditioning by NO is not known. It is likely that NO is involved in opening of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels. We hypothesized that NO is an important trigger for the opening of mitoK(ATP) channels in the late phase of preconditioning and inducible nitric oxide synthase (iNOS) up-regulation via NF kappa B plays a critical role in diazoxide-induced cardioprotection. To examine this, diazoxide (7 mg/kg) was administered to wild-type (WT) mice and mice lacking the gene 24 hours before 40 minutes of global ischemia. Hearts were perfused in a Langendorff mode and effects of activation of mitoK(ATP) channel and other interventions on functional, biochemical and pathological changes in ischemic hearts were assessed. In hearts from WT mice treated diazoxide, left-ventricular-developed pressure, end-diastolic pressure and coronary flow were significantly improved after ischemia/reperfusion (I/R); lactate dehydrogenase (LDH) release was also significantly decreased, while ATP contents were significantly higher. Administration of 5-HD, a specific blocker of mitoK(ATP) channel or l -NAME, an inhibitor of iNOS before I/R, during diazoxide-pretreatment completely blocked the late cardioprotection against ischemia. Late cardioprotection was also blocked by inhibition of either PKC- delta by rottlerin or NF kappa B by DDTC before diazoxide pretreatment. Diazoxide pretreatment significantly increased nuclear translocation of p65 which was blocked by protein kinase C (PKC) or nitric oxide synthase (NOS) inhibition. Diazoxide was totally inefffective in iNOS knockout mice. These results suggest that diazoxide activates NF kappa B via PKC signaling pathway and that leads to iNOS up-regulation after 24 hours. NO which is generated upon ischemic stress triggers the opening of mitoK(ATP)channel as an end effector of cardioprotection during late PC.
Wang
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Y
Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267-0529, USA.
Kudo
M
M
Xu
M
M
Ayub
A
A
Ashraf
M
M
D000098:Acetophenones / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D001783:Blood Flow Velocity; D001794:Blood Pressure; D002467:Cell Nucleus / Q000378:metabolism; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006352:Heart Ventricles / Q000378:metabolism; D006880:Hydroxy Acids / Q000494:pharmacology; D007511:Ischemia / Q000378:metabolism; D019157:Ischemic Preconditioning, Myocardial; D007527:Isoenzymes / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism / Q000494:pharmacology; D051745:Protein Kinase C-delta; D015427:Reperfusion Injury; D015398:Signal Transduction; D013997:Time Factors; D051996:Transcription Factor RelA; D015854:Up-Regulation
D000098:Acetophenones; D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D006880:Hydroxy Acids; D007527:Isoenzymes; D016328:NF-kappa B; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D051996:Transcription Factor RelA; D009569:Nitric Oxide; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; C085746:rottlerin; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C497259:Prkcd protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D003981:Diazoxide; D019331:NG-Nitroarginine Methyl Ester