title: Opening of the adenosine triphosphate-sensitive potassium channel attenuates cardiac remodeling induced by long-term inhibition of nitric oxide synthesis: role of 70-kDa S6 kinase and extracellular signal-regulated kinase.
abstract: OBJECTIVE
  We examined whether the adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channel openers (KCOs) block myocardial hypertrophy and whether the 70-kDa S6 kinase (p70S6K) or extracellular signal-regulated kinase (ERK)-dependent pathway is involved.
  
  
  BACKGROUND
  Long-term inhibition of nitric oxide (NO) synthesis induces cardiac hypertrophy independent of blood pressure, by increasing protein synthesis in vivo. The KCOs attenuate calcium overload and confer cardioprotection against ischemic stress, thereby preventing myocardial remodeling.
  
  
  METHODS
  Twelve Wistar-Kyoto rat groups underwent eight weeks of the drug treatment in combination with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME), the inactive isomer D(omega)-nitro-L-arginine methyl ester, KCOs (nicorandil, 3 and 10 mg/kg per day, or JTV-506, 0.3 mg/kg per day), or the K(ATP) channel blocker glibenclamide. The L-NAME was also used with hydralazine, the p70S6K inhibitor rapamycin, or the mitogen-activated protein kinase inhibitor PD98059. Finally, the left ventricular weight (LVW) to body weight (BW) ratio was quantified, followed by histologic examination and kinase assay.
  
  
  RESULTS
  The L-NAME increased blood pressure and LVW/BW, as compared with the control agent. The KCOs and hydralazine equally cancelled the increase in blood pressure, whereas only KCOs blocked the increase in LVW/BW and myocardial hypertrophy induced by L-NAME. The L-NAME group showed both p70S6K and ERK activation in the myocardium (2.3-fold and 2.0-fold increases, respectively), as compared with the control group, which was not reversed by hydralazine. Selective inhibition of either p70S6K or ERK blocked myocardial hypertrophy. The KCOs prevented the increase in activity only of p70S6K. Glibenclamide reversed the effect of nicorandil in the presence of L-NAME.
  
  
  CONCLUSIONS
  The KCOs modulate p70S6K, not ERK, to attenuate myocardial hypertrophy induced by long-term inhibition of NO synthesis in vivo.
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Sanada
authors.forename: Koichi
authors.initials: K
authors.lastname: Node
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Ogita
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Minamino
authors.forename: Masanori
authors.initials: M
authors.lastname: Asakura
authors.forename: Yulin
authors.initials: Y
authors.lastname: Liao
authors.forename: Akiko
authors.initials: A
authors.lastname: Ogai
authors.forename: Jiyoong
authors.initials: J
authors.lastname: Kim
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight; D006332:Cardiomegaly / Q000139:chemically induced; D005905:Glyburide / Q000494:pharmacology; D006830:Hydralazine / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020108:Nicorandil / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D011921:Rats, Inbred WKY; D019893:Ribosomal Protein S6 Kinases / Q000502:physiology*
chemical_list: D015221:Potassium Channels; D020108:Nicorandil; D006830:Hydralazine; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D019893:Ribosomal Protein S6 Kinases; D020928:Mitogen-Activated Protein Kinases; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester