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.