title: Nitrite Reduces Ischemia-Induced Ventricular Arrhythmias by Attenuating Connexin 43 Dephosphorylation in Rats.
abstract: BACKGROUND
  Ventricular arrhythmias induced by ischemic heart disease are the main cause of sudden cardiac death. Ischemia can cause life-threatening arrhythmias by modulating connexin 43 (Cx43), a principal cardiac gap junction channel protein. The present study investigates whether nitrite can attenuate ischemia-induced ventricular arrhythmias and dephosphorylation of Cx43 in a rat model.
  
  
  METHODS
  Rats were medicated with normal saline (control, n = 10), nitrite (0.015, 0.15, and 1.5 mg/kg, n = 9 or 10 each), and 0.15 mg/kg nitrite with either the nitric oxide scavenger 2-(4-carboxyphenyl)-4, 4, 5, 5-tetramethylimidazoline-1-oxyl-3-oxide, sodium salt (cPTIO; n = 9) or allopurinol (xanthine oxidoreductase inhibitor, n = 9). We determined the severity of ventricular arrhythmias based on arrhythmia scores and levels of phosphorylated Cx43.
  
  
  RESULTS
  The median arrhythmia score may have been lower in the group given 0.15 mg/kg nitrite (4 [interquartile range {IQR}, 4-5]) than that in the control group (7.5 [IQR, 5.25-8]; P = 0.013). There was no difference among the control, the given 0.015 mg/kg nitrite (7 [IQR, 5-8]), and 1.5 mg/kg nitrite (7 [IQR, 5.5-7.75]; P = 0.95). The arrhythmia scores in the cPTIO (6 [IQR, 5-8]; P = 0.030) and allopurinol (7 [IQR, 5-8]; P = 0.005) groups may have been higher than that in 0.15 mg/kg nitrite group. Immunoblotting revealed that the level of phosphorylated Cx43 in the group given 0.15 mg/kg nitrite, but not in the other treated groups, was significantly higher compared with the control group (P = 0.007).
  
  
  CONCLUSIONS
  Nitrite may have attenuated acute ischemia-induced ventricular arrhythmias and Cx43 dephosphorylation in rats. Nitric oxide, which might be generated by xanthine oxidoreductase via nitrite reduction, appears to play a crucial role in this antiarrhythmic effect.
authors.affiliation: From the Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Maruyama
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Hirata
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Tokinaga
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Kawaguchi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Yamakage
mesh_terms: D000493:Allopurinol / Q000627:therapeutic use; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology; D001784:Blood Gas Analysis; D018031:Connexin 43 / Q000187:drug effects* / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D016166:Free Radical Scavengers / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000627:therapeutic use; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy*; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012977:Sodium Nitrite / Q000627:therapeutic use*; D018754:Ventricular Dysfunction / Q000188:drug therapy* / Q000209:etiology
chemical_list: D018031:Connexin 43; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; C580592:Gja1 protein, rat; D007093:Imidazoles; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D009569:Nitric Oxide; D000493:Allopurinol; D012977:Sodium Nitrite