Exogenous luminal nitric oxide exacerbates esophagus tissue damage in a reflux esophagitis model of rats

Fumitake Ishiyama, Katsunori Iijima, Kiyotaka Asanuma, Nobuyuki Ara, Jun Yoshitake, Yasuhiko Abe, Tomoyuki Koike, Akira Imatani, Shuichi Ohara, Tooru Shimosegawa

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


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. Material and 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.

Original languageEnglish
Pages (from-to)527-537
Number of pages11
JournalScandinavian Journal of Gastroenterology
Issue number5
Publication statusPublished - 2009 May


  • Animal model
  • Dietary nitrate
  • Nitric oxide
  • Reflux esophagitis


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