Low endotoxemia prevents the reduction of gastric blood flow induced by NSAIDs: role of nitric oxide

The role of nitric oxide (NO) in the effects of low endotoxemia on gastric damage and blood flow has been evaluated in indomethacin-treated rats. Pretreatment (−1 h) with endotoxin (40 μg kg−1) reduced gastric damage induced by indomethacin (20 mg kg−1) in conscious rats. Endotoxin prevented the reduction in gastric blood flow (laser Doppler flowmetry) induced by indomethacin in pentobarbital-anaesthetised rats. Pretreatment with an NO-synthase (NOS) inhibitor (L-NAME, 1 mg kg−1) reversed the protective effect of endotoxin on gastric blood perfusion. Endotoxin did not modify the expression of mRNA for endothelial NOS or inducible NOS in the gastric corpus when evaluated 1 h postinjection. However, a 3.8-fold increase in inducible NOS mRNA and a 61% reduction in endothelial NOS mRNA were observed in the gastric corpus 4 h after endotoxin administration. Evaluation of both total and Ca2+-dependent NOS activity by analysing the rate of conversion of L-arginine to L-citrulline in gastric corpus homogenates showed no differences between animals treated with endotoxin and those treated with saline 1 or 4 h beforehand. Ca2+-independent NOS activity was almost non-apparent in control as well as in endotoxin-treated rats at all the time points analysed. Low endotoxemia preserves blood perfusion and protects the gastric mucosa against the deleterious effects of indomethacin through the endogenous NO release. NO synthesis in response to endotoxin does not involve the inducible NOS, but probably depends on the post-translational/biochemical regulation in vivo of a Ca2+-dependent NOS, most probably endothelial NOS. British Journal of Pharmacology (2003) 139, 263–270. doi:10.1038/sj.bjp.0705239