Diffusion of cytotoxic concentrations of nitric oxide generated luminally at the gastro-oesophageal junction of rats

Kiyotaka Asanuma ¹, Katsunori Iijima ^2*, Hideaki Sugata ¹, Shuichi Ohara ², Tooru Shimosegawa ² and Tetsuhiko Yoshimura ¹

¹ Laboratory of Applied Biomedicinal Chemistry, Institute for Life Support Technology, Yamagata, Japan
² Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

^* To whom correspondence should be addressed. E-mail: jiijima{at}int3.med.tohoku.ac.jp.

Accepted 20 April 2005

Abstract

Background: In human, high concentrations of nitric oxide are generated luminally at the gastro- esophageal junction through the entero-salivary re- circulation of dietary nitrate.

Aim: To investigate whether luminal nitric oxide can diffuse into the adjacent digestive tissue and alter the tissue integrity.

Methods: We designed an animal model using Wistar rats in which physiological concentrations of nitrite and acidified ascorbic acid were administered separately so that the two reactants first meet to form nitric oxide at the gastro-esophageal junction. The luminal or tissue concentration of nitric oxide was measured with an electrode or an electron paramagnetic resonance spectrometer, respectively. The concentration of glutathione in the tissue was measured as a marker of nitrosative stress.

Results: High concentrations of luminal nitric oxide were generated locally at the gastro-esophageal junction of the nitrite-administered rats, reproducing a phenomenon observed in human. High levels of nitric oxide were also detected largely in the superficial epithelium of the gastro-esophageal junction. The concentration of tissue glutathione at the gastro-esophageal junction was significantly lower in nitrite-administered rats compared to control rats, whereas that in the distal stomach was similar between the two rat groups.

Conclusions: Using an animal model, this study demonstrated that nitric oxide generated in the lumen diffuses into the adjacent gastric tissue to a substantial degree, leading to localized consumption of glutathione in the tissue. Nitrosative stress induced by this mechanism may be involved in the high prevalence of inflammation and metaplasia, and subsequent development of neoplastic disease at that site.

Keywords: dietary nitrate, gastro-oesophageal junction, nitric oxide

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