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

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 Ϯ 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 Ϯ 0.16; 6 h, 13.3 Ϯ 3.3 nmol/g tissue/30 min; and PGE2: control, 288 Ϯ 16; 6 h, 806 Ϯ 15 pg/g tissue). Pretreatment with 1400W decreased the increase in NO level without any effect on the PGE2 level (NO, 4.0 Ϯ 0.4 nmol/g tissue/30 min; PGE2, 788 Ϯ 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 LPStreated 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.

Heterogenous vasodilator pathways underlie flow-mediated dilation in men and women

“…Alternatively, this observation could also indicate an effect of crosstalk between vasoactive substances released by the endothelium. For example, PGs may inhibit NO (56,57) and endothelin (34) whereas NO stimulates PG production (8,47) and inhibits endothelin secretion (6). In humans, Taddei et al (54) found that the inhibitory influence of L-NMMA as well as the potentiating effects of L-arginine on the forearm dilatory response to acetylcholine was abolished in hypertensive adults and could only be restored through inhibition of cylcooxygenase.…”

Prostaglandin F2α (PGF2α) stimulates PTGS2 expression and PGF2α synthesis through NFKB activation via reactive oxygen species in the corpus luteum of pseudopregnant rats

“…NS-398 had no effects on Ptgs2 mRNA expression in our preliminary experiments. It is also verified by a manufacturer that NS-398 administration in vivo causes no significant effects on mRNA and protein expression of PTGS2 in the rats (Uno et al 2004).…”

Gastric damage induced by different doses of indomethacin in rats is variably affected by inhibiting iNOS or leukocyte infiltration

“…Minor doses, such as 1.5 mg.kg -1 did not induced NO decrease. Meanwhile, major doses, such as 10 mg.kg -1 induced NO decrease [24]. That cross-talk between prostaglandins and nitric oxide pathways could be responsible for the observed gastric protection after aminoguanidine in rats that received indomethacin at 20 mg.kg -1 , but not in those that received indomethacin at 5 mg.kg -1 .…”