title: Inhibition of Succinate Dehydrogenase by Diazoxide Is Independent of the ATP-Sensitive Potassium Channel Subunit Sulfonylurea Type 1 Receptor.
abstract: BACKGROUND
  Diazoxide maintains myocyte volume and contractility during stress via an unknown mechanism. The mechanism of action may involve an undefined (genotype unknown) mitochondrial ATP-sensitive potassium channel and is dependent on the ATP-sensitive potassium channel subunit sulfonylurea type 1 receptor (SUR1). The ATP-sensitive potassium channel openers have been shown to inhibit succinate dehydrogenase (SDH) and a gene for a portion of SDH has been found in the SUR intron. Diazoxide may be cardioprotective via inhibition of SDH, which can form part of an ATP-sensitive potassium channel or share its genetic material. This study investigated the role of inhibition of SDH by diazoxide and its relationship to the SUR1 subunit.
  
  
  METHODS
  Mitochondria were isolated from wild-type and SUR1 knockout mice. Succinate dehydrogenase activity was measured by spectrophotometric analysis of 2,6-dichloroindophenol reduction for 20 minutes as the relative change in absorbance over time. Mitochondria were treated with succinate (20 mM), succinate + 1% dimethylsulfoxide, succinate + malonate (8 mM) (competitive inhibitor of SDH), or succinate + diazoxide (100 μM).
  
  
  RESULTS
  Both malonate and diazoxide inhibit SDH activity in mitochondria of wild-type mice and in mice lacking the SUR1 subunit (p < 0.05 vs control).
  
  
  CONCLUSIONS
  The ability of DZX to inhibit SDH persists even after deletion of the SUR1 gene. Therefore, the enzyme complex SDH is not dependent on the SUR1 gene. The inhibition of SDH by DZX can play a role in the cardioprotection afforded by DZX; however, this role is independent of the ATP-sensitive potassium channel subunit SUR1.
authors.affiliation: Department of Surgery, Division of Cardiothoracic Surgery, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Anastacio
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: Kanter
authors.forename: Angela D
authors.initials: AD
authors.lastname: Keith
authors.forename: Richard B
authors.initials: RB
authors.lastname: Schuessler
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Lawton
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D003981:Diazoxide / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D011955:Receptors, Drug / Q000378:metabolism*; D013053:Spectrophotometry; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064233:Sulfonylurea Receptors; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; C577508:Abcc8 protein, mouse; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014665:Vasodilator Agents; D013385:Succinate Dehydrogenase; D003981:Diazoxide
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