title: Cardioprotective mechanism of diazoxide involves the inhibition of succinate dehydrogenase.
abstract: BACKGROUND
  The adenosine triphosphate-sensitive potassium (KATP) channel opener, diazoxide, preserves myocyte volume homeostasis and contractility during stress via an unknown mechanism. Pharmacologic overlap has been suggested between succinate dehydrogenase (SDH) activity and KATP channel modulators. Diazoxide may be cardioprotective due to the inhibition of SDH which may form a portion of the mitochondrial KATP channel. To determine the role of inhibition of SDH in diazoxide's cardioprotection, this study utilized glutathione to prevent the inhibition of SDH.
  
  
  METHODS
  SDH activity was measured in isolated mitochondria exposed to succinate (control), malonate (inhibitor of succinate dehydrogenase), diazoxide, and varying concentrations of glutathione alone or in combination with diazoxide. Enzyme activity was measured by spectrophotometric analysis. To evaluate myocyte volume and contractility, cardiac myocytes were superfused with Tyrode's physiologic solution (Tyrode's) (20 minutes), followed by test solution (20 minutes), including Tyrode's, hyperkalemic cardioplegia (stress), cardioplegia + diazoxide, cardioplegia + diazoxide + glutathione, or glutathione alone; followed by Tyrode's (20 minutes). Myocyte volume and contractility were recorded using image grabbing software.
  
  
  RESULTS
  Both malonate and diazoxide inhibited succinate dehydrogenase. Glutathione prevented the inhibition of succinate dehydrogenase by diazoxide in a dose-dependent manner. The addition of diazoxide prevented the detrimental myocyte swelling due to cardioplegia alone and this benefit was lost with the addition of glutathione. However, glutathione elicited an independent cardioprotective effect on myocyte contractility.
  
  
  CONCLUSIONS
  The ability of diazoxide to provide beneficial myocyte homeostasis during stress involves the inhibition of succinate dehydrogenase, which may also involve the opening of a purported mitochondrial adenosine triphosphate sensitive potassium channel.
authors: Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Melissa M
authors: MM
authors: Anastacio
authors: Evelyn M
authors: EM
authors: Kanter
authors: Carol
authors: C
authors: Makepeace
authors: Angela D
authors: AD
authors: Keith
authors: Haixia
authors: H
authors: Zhang
authors: Richard B
authors: RB
authors: Schuessler
authors: Colin G
authors: CG
authors: Nichols
authors: Jennifer S
authors: JS
authors: Lawton
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D003981:Diazoxide / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000201:enzymology; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D009997:Osmotic Pressure; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011897:Random Allocation; D012680:Sensitivity and Specificity; D013385:Succinate Dehydrogenase / Q000187:drug effects* / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D013385:Succinate Dehydrogenase; D003981:Diazoxide
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