In vivo study on cross talk between inducible nitric-oxide synthase and cyclooxygenase in rat gastric mucosa: Effect of cyclooxygenase activity on nitric oxide production

Kaname Uno, Yoshihito Iuchi, Junichi Fujii, Hideaki Sugata, Katsunori Iijima, Katsuaki Kato, Tooru Shimosegawa, Tetsuhiko Yoshimura

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38 Citations (Scopus)

Abstract

The integrity of gastric mucosa during endotoxemia is maintained by the balance of inflammatory mediators, such as prostanoids originated from cyclooxygenase-2 (COX-2) and nitric oxide (NO) from inducible nitric-oxide synthase (iNOS). Thus, we elucidated in vivo cross talk between prostanoids and NO in gastric mucosa during endotoxemia, using an iNOS-specific inhibitor, N-(3-(aminomethyl)benzyl)acetamidine (1400W); a nonspecific COX inhibitor, indomethacin; and a COX-2-specific inhibitor, N-(2-[cyclohexyloxy]-4-nitrophenyl)methanesulfonamide (NS-398). Gastric mucosal NO and prostaglandin E2 (PGE2), a predominant product of COX, expressed as mean ± S.D. of five rats per group, were assayed by electron paramagnetic resonance spectrometry and enzyme immunoassay technique, respectively. The levels of NO and PGE2 increased gradually up to 6 h after administration of bacterial lipopolysaccharide (LPS) (NO: control, 0.35 ± 0.16; 6 h, 13.3 ± 3.3 nmol/g tissue/30 min; and PGE2: control, 288 ± 16; 6 h, 806 ± 15 pg/g tissue). Pretreatment with 1400W decreased the increase in NO level without any effect on the PGE2 level (NO, 4.0 ± 0.4 nmol/g tissue/30 min; PGE2, 788 ± 26 pg/g tissue). In contrast, treatment with indomethacin and NS-398 inhibited not only PGE2 level but also NO level in a dose-dependent manner without any significant effect on both iNOS and COX protein and mRNA expression. These results demonstrate that in the LPS-treated rat gastric mucosa, PGE2 enhances the release of NO after activation of iNOS, although NO produced by iNOS does not stimulate the release of PGE2 by COXs. The effect of COX activity on iNOS-NO pathway can be important in the regulation of gastric mucosal integrity in inflammatory states.

Original languageEnglish
Pages (from-to)995-1002
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume309
Issue number3
DOIs
Publication statusPublished - 2004 Jun

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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