title: Exogenous luminal nitric oxide exacerbates esophagus tissue damage in a reflux esophagitis model of rats.
abstract: OBJECTIVE
  Cytotoxic concentrations of nitric oxide are generated luminally at the gastroesophageal junction through the entero-salivary recirculation of dietary nitrate in humans. The site of luminal nitric oxide generation shifts to the lower esophagus when gastric acid is refluxed into the esophagus. The aim of this study was to investigate the influence of persistent administration of exogenous nitric oxide on esophageal damage.
  
  
  METHODS
  0.1% sodium nitrite and/or 1% ascorbic acid was administered in an established rat acid-refluxed esophagitis model. Co-administration of both reactants in this model is thought to induce high concentrations of nitric oxide luminally in the esophagus by an acid-catalyzed chemical reaction when refluxed gastric acid is present. The tissue damage was evaluated by a macroscopic lesion index and myeloperoxidase activity. Nitrotyrosin was assessed immunohistochemically as a footprint of peroxynitrite formation.
  
  
  RESULTS
  Co-administration of sodium nitrite and ascorbic acid induced a 4- to 5-fold increase in the esophageal damage compared with baseline reflux esophagitis, while the damage was unchanged when either of the reagents alone was given. Nitrotyrosine was strongly stained in the tissue from the co-administration. Treatment of superoxide scavengers efficiently prevented the exacerbation of esophageal damage by exogenous nitric oxide exposure, suggesting an essential role of superoxide in esophageal damage.
  
  
  CONCLUSIONS
  Exogenous luminal nitric oxide greatly exacerbated the tissue damage of reflux esophagitis. Diffusion of the luminal nitric oxide into the adjacent superoxide-enriched inflamed tissue of the esophagus could lead to the production of the highly toxic agent peroxynitrite, thus causing exacerbation of the esophageal damage.
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Fumitake
authors.initials: F
authors.lastname: Ishiyama
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iijima
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Asanuma
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ara
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshitake
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Abe
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Koike
authors.forename: Akira
authors.initials: A
authors.lastname: Imatani
authors.forename: Shuichi
authors.initials: S
authors.lastname: Ohara
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001205:Ascorbic Acid / Q000009:adverse effects / Q000494:pharmacology*; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004942:Esophagitis, Peptic / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D004943:Esophagogastric Junction / Q000187:drug effects* / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D009569:Nitric Oxide / Q000009:adverse effects* / Q000494:pharmacology; D009853:Omeprazole / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity
chemical_list: D009569:Nitric Oxide; D009195:Peroxidase; D009853:Omeprazole; D001205:Ascorbic Acid