title: Increased tolerance to stress in cardiac expressed gain-of-function of adenosine triphosphate-sensitive potassium channel subunit Kir6.1.
abstract: The adenosine triphosphate-sensitive potassium (KATP) channel opener diazoxide (DZX) prevents myocyte volume derangement and reduced contractility secondary to stress. KATPchannels are composed of pore-forming (Kir6.1 or Kir6.2) and regulatory (sulfonylurea receptor, SUR1 or SUR2) subunits. Gain of function (GOF) of Kir6.1 subunits has been implicated in cardiac pathology in Cantu syndrome in humans (cardiomegaly, lymphedema, and pericardial effusions). We hypothesized that GOF of Kir6.1 subunits would result in altered myocyte response to stress.
  
  
  
  Isolated cardiac myocytes from wild type (WT) and transgenic Kir6.1GOF mice were exposed to Tyrode's physiologic solution for 20 min, test solution (Tyrode's or stress [hyperkalemic cardioplegia {CPG, known myocyte stress}] +/- KATPchannel opener DZX), followed by Tyrode's for 20 min. Myocyte volume and contractility were measured and compared.
  
  
  
  WT myocytes demonstrated significant swelling in response to stress, but significantly less swelling was seen in Kir6.1GOF myocytes. DZX prevented swelling secondary to CPG in WT but resulted in a nonsignificant reduction in swelling in Kir6.1GOF myocytes. Both WT and Kir6.1GOF myocytes demonstrated a reduction in contractility during stress, although this was only significant in Kir6.1GOF myocytes. DZX was not associated with an improvement in contractility in Kir6.1GOF myocytes following stress.
  
  
  
  Similar to previous results in Kir6.1(-/-) myocytes, Kir6.1GOF myocytes demonstrate resistance (less volume derangement) to stress of cardioplegia. Understanding the role of Kir6.1 in myocyte response to stress may aid in the treatment of patients with Cantu syndrome and warrants further investigation.
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Henn
authors.affiliation: Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: M Burhan
authors.initials: MB
authors.lastname: Janjua
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Haixia
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: Kanter
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Carol M
authors.initials: CM
authors.lastname: Makepeace
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Schuessler
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri. Electronic address: jlawton4@jhmi.edu.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Lawton
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology*; D048429:Cell Size / Q000187:drug effects; D003981:Diazoxide / Q000494:pharmacology; D005819:Genetic Markers; D006983:Hypertrichosis / Q000235:genetics / Q000503:physiopathology*; D054086:KATP Channels / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D010009:Osteochondrodysplasias / Q000235:genetics / Q000503:physiopathology*; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D005819:Genetic Markers; D054086:KATP Channels; D014665:Vasodilator Agents; C092520:uK-ATP-1 potassium channel; D003981:Diazoxide
keywords: Cantu syndrome; Diazoxide; Myocardial stress; Potassium channel