Effective pharmacotherapy against oxidative injury: alternative utility of an ATP-sensitive potassium channel opener.
Cardiomyocyte viability following ischemia-reperfusion critically depends on mitochondrial function. In this regard, potassium channel openers (KCOs) targeting mitochondria have emerged as powerful cardioprotective agents when applied at the onset of ischemia. However, it is controversial whether openers are still protective when applied at the onset of reoxygenation. Here, H9c2 cardiomyocytes and mitochondria isolated from the rat heart ventricle were subjected to ischemia-reoxygenation or oxidative stress in the absence or presence of 100 microM diazoxide, a potassium channel opener. Ischemia-reoxygenation or oxidative stress significantly reduced cell viability, induced structural damage in association with increased mitochondrial protein release, and impaired oxidative phosphorylation. However, treatment with diazoxide before anoxia or at the onset of reoxygenation, as well as during oxidative stress, prevented cell death and mitochondrial dysfunction and preserved cellular and mitochondrial structural integrity. These protective effects were blocked by 5-hydroxydecanoate. Thus, treatment with potassium channel openers even at the time of reoxygenation may provide a significant protection of the myocardium. The protective mechanism is at least in part endogenous to the mitochondria because protection was also observed in isolated mitochondria.
Ozcan
Cevher
C
Section of Cardiovascular Diseases, Yale University School of Medicine, New Haven, CT, USA.
Terzic
Andre
A
Bienengraeber
Martin
M
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D015687:Cell Hypoxia; D002460:Cell Line; D019069:Cell Respiration / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003402:Creatine Kinase / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D054086:KATP Channels / Q000819:agonists*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats
D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D054086:KATP Channels; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; D003981:Diazoxide