title: Diazoxide Cardioprotection Is Independent of Adenosine Triphosphate-Sensitive Potassium Channel Kir6.1 Subunit in Response to Stress.
abstract: BACKGROUND
  The sarcolemmal adenosine triphosphate-sensitive potassium channel (sK(ATP)), composed primarily of potassium inward rectifier (Kir) 6.2 and sulfonylurea receptor 2A subunits, has been implicated in cardiac myocyte volume regulation during stress; however, it is not involved in cardioprotection by the adenosine triphosphate-sensitive potassium channel (K(ATP)) channel opener diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide [DZX]). Paradoxically, the sK(ATP) channel subunit Kir6.2 is necessary for detrimental myocyte swelling secondary to stress. The Kir6.1 subunit can also contribute to K(ATP) channels in the heart, and we hypothesized that this subunit might play a role in myocyte volume regulation in response to stress.
  
  
  METHODS
  Isolated cardiac myocytes from either wild-type mice or mice lacking the Kir6.1 subunit (Kir6.1[-/-]) were exposed to control Tyrode's solution (TYR) for 20 minutes, test solution (TYR, hypothermic hyperkalemic cardioplegia [CPG], or CPG + K(ATP) channel opener DZX [CPG + DZX]) for 20 minutes, followed by TYR for 20 minutes. Myocyte volume and contractility were measured and analyzed.
  
  
  RESULTS
  Both wild-type and Kir6.1(-/-) myocytes demonstrated substantial swelling during exposure to stress (CPG), which was prevented by DZX. Wild-type myocytes also demonstrated reduced contractility during stress of CPG that was prevented by DZX. However, Kir6.1(-/-) myocytes did not show reduced contractility during stress.
  
  
  CONCLUSIONS
  These data indicate that K(ATP) channel subunit Kir6.1 is not necessary for DZX's maintenance of cell volume during the stress of CPG. The absence of Kir6.1 does not affect the contractile properties of myocytes during stress, suggesting the absence of Kir6.1 improves myocyte tolerance to stress via an unknown mechanism.
authors: Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St Louis, MO.
authors: Matthew C
authors: MC
authors: Henn
authors: Washington University School of Medicine, St Louis, MO.
authors: M Burhan
authors: MB
authors: Janjua
authors: Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO.
authors: Haixia
authors: H
authors: Zhang
authors: Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St Louis, MO.
authors: Evelyn M
authors: EM
authors: Kanter
authors: Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St Louis, MO.
authors: Carol M
authors: CM
authors: Makepeace
authors: Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St Louis, MO.
authors: Richard B
authors: RB
authors: Schuessler
authors: Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO.
authors: Colin G
authors: CG
authors: Nichols
authors: Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St Louis, MO. Electronic address: lawtonj@wustl.edu.
authors: Jennifer S
authors: JS
authors: Lawton
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D048429:Cell Size / Q000187:drug effects*; D003981:Diazoxide / Q000494:pharmacology*; D054086:KATP Channels / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects* / Q000502:physiology
chemical_list: D015415:Biomarkers; D002316:Cardiotonic Agents; D054086:KATP Channels; C092520:uK-ATP-1 potassium channel; D003981:Diazoxide