Protective role of nitric oxide in indomethacin-induced gastric ulceration by a mechanism independent of gastric acid secretion.

Gastric ulceration was induced in rats by i.p. injection of the non-steroidal anti-inflammatory drug (NSAID), indomethacin (IND) (30 mg kg(-1)). Pyloric ligation was carried out in each animal before injection to enable collection of the gastric juice. Three hours later, the animals were killed and their stomachs were removed. In the gastric juice, the amounts of mucin, pepsin and HCl were assessed. Gastric mucosa were scrapped for the determination of nitric oxide (NO) (as nitrite) after evaluation of the gastric ulcer index. The influence of arginine (ARG) (300 mg kg(-1)), a NO precursor, N(G)-nitro- l -arginine methyl ester (l -NAME) (50 mg kg(-1)), a non-selective constitutive nitric oxide synthase/inducible nitric oxide synthase (cNOS/iNOS) inhibitor, and the selective iNOS inhibitor aminoguanidine (AMG) (50 mg kg(-1)) were studied. Each NO modulator was injected i.p. 30 min before IND administration. Results indicated that IND elevated gastric acidity by 80% of the normal group, decreased non-significantly mucosal nitrite by 22% and exhibited a remarkably high ulcer index (chi = 17). Neither mucin nor pepsin levels were significantly altered. In comparison with the IND group, pretreatment with l -NAME caused a significant decrease in gastric HCl, further decrease in mucosal nitrite (50% of normal) and a two-fold increase in the ulcer index score (chi = 34), despite the decrease in HCl. AMG did not alter gastric acidity, decreased mucosal nitrite by 38% of the normal value and failed to alter significantly the ulcer index of IND. On the other hand, pretreatment with ARG did not alter the gastric acidity and raised mucosal nitrite by 10% above normal. Surprisingly, ARG improved the gastric ulcer score (chi = 1) almost similar to the normal score (chi = zero). Therefore, this study creates a new pathway for the potential treatment of NSAID gastric ulceration through modulation of NO synthesis, regardless of the effect on gastric acidity.