title: Potassium channel openers protect cardiac mitochondria by attenuating oxidant stress at reoxygenation.
abstract: K(+) channel openers have been recently recognized for their ability to protect mitochondria from anoxic injury. Yet the mechanism responsible for mitochondrial preservation under oxidative stress is not fully understood. Here, mitochondria were isolated from rat hearts and subjected to 20-min anoxia, followed by reoxygenation. At reoxygenation, increased generation of reactive oxygen species (ROS) was associated with reduced ADP-stimulated oxygen consumption, blunted ATP production, and disrupted mitochondrial structural integrity coupled with cytochrome c release. The prototype K(+) channel opener diazoxide markedly reduced mitochondrial ROS production at reoxygenation with a half-maximal effect of 29 microM. Diazoxide also preserved oxidative phosphorylation and mitochondrial membrane integrity, as indicated by electron microscopy and reduced cytochrome c release. The protective effect of diazoxide was reproduced by the structurally distinct K(+) channel opener nicorandil and antagonized by 5-hydroxydecanoic acid, a short-chain fatty acid derivative and presumed blocker of mitochondrial ATP-sensitive K(+) channels. Opener-mediated mitochondrial protection was simulated by the free radical scavenger system composed of superoxide dismutase and catalase. However, the effect of openers on ROS production was maintained in nominally K(+)-free medium in the presence or absence of the K(+) ionophore valinomycin and was mimicked by malonate, a modulator of the mitochondrial redox state. This suggests the existence of a K(+) conductance-independent pathway for mitochondrial protection targeted by K(+) channel openers. Thus the cardioprotecive mechanism of K(+) channel openers includes direct attenuation of mitochondrial oxidant stress at reoxygenation.
authors.affiliation: Department of Medicine, Molecular Pharmacology, and Experimental Therapeutics, Mayo Clinic, Mayo Foundation, Rochester, Minnesota 55905, USA.
authors.forename: Cevher
authors.initials: C
authors.lastname: Ozcan
authors.forename: Martin
authors.initials: M
authors.lastname: Bienengraeber
authors.forename: Petras P
authors.initials: PP
authors.lastname: Dzeja
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D016166:Free Radical Scavengers / Q000378:metabolism; D006880:Hydroxy Acids / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D020108:Nicorandil / Q000494:pharmacology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000819:agonists / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D003574:Cytochrome c Group; D003652:Decanoic Acids; D016166:Free Radical Scavengers; D006880:Hydroxy Acids; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D020108:Nicorandil; D000244:Adenosine Diphosphate; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; D013385:Succinate Dehydrogenase; D003981:Diazoxide; D011188:Potassium