Opening of the mitoKATP channel and decoupling of mitochondrial complex II and III contribute to the suppression of myocardial reperfusion hyperoxygenation.
Diazoxide, a mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel opener, protects the heart from ischemia-reperfusion injury. Diazoxide also inhibits mitochondrial complex II-dependent respiration in addition to its preconditioning effect. However, there are no prior studies of the role of diazoxide on post-ischemic myocardial oxygenation. In the current study, we determined the effect of diazoxide on the suppression of post-ischemic myocardial tissue hyperoxygenation in vivo, superoxide (O(2)(-*)) generation in isolated mitochondria, and impairment of the interaction between complex II and complex III in purified mitochondrial proteins. It was observed that diazoxide totally suppressed the post-ischemic myocardial hyperoxygenation. With succinate but not glutamate/malate as the substrate, diazoxide significantly increased ubisemiquinone-dependent O(2)(-*) generation, which was not blocked by 5-HD and glibenclamide. Using a model system, the super complex of succinate-cytochrome c reductase (SCR) hosting complex II and complex III, we also observed that diazoxide impaired complex II and its interaction with complex III with no effect on complex III. UV-visible spectral analysis revealed that diazoxide decreased succinate-mediated ferricytochrome b reduction in SCR. In conclusion, our results demonstrated that diazoxide suppressed the in vivo post-ischemic myocardial hyperoxygenation through opening the mitoK(ATP) channel and ubisemiquinone-dependent O(2)(-*) generation via inhibiting mitochondrial complex II-dependent respiration.
The Center for Biomedical EPR Spectroscopy and Imaging, Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
Bin
B
Liu
Xuehai
X
Zhu
Chwen-Lih
CL
Chen
Keli
K
Hu
Harold M
HM
Swartz
Yeong-Renn
YR
Chen
Guanglong
G
He
D000818:Animals; D003981:Diazoxide / Q000494:pharmacology*; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D008297:Male; D008314:Malonates / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009574:Nitro Compounds / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000819:agonists* / Q000378:metabolism / Q000502:physiology; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology
D008314:Malonates; D009574:Nitro Compounds; D015221:Potassium Channels; D011422:Propionates; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; C030290:malonic acid; D042963:Electron Transport Complex II; D014450:Electron Transport Complex III; D003981:Diazoxide; C015392:3-nitropropionic acid