We have reported that increases in lipid peroxide (LPO) formation, nonprotein sulfhydryl (NP-SH) oxidation, and inducible NO synthase (iNOS) activity and a decrease in constitutive NO synthase (cNOS) activity in the gastric mucosa of rats with water immersion restraint (WIR) stress are closely related to gastric mucosal lesion development. Peroxynitrite, which is produced by the reaction of nitric oxide (NO) with superoxide anion, can initiate intracellular LPO formation and NP-SH oxidation, resulting in producing an extreme cellular membrane damage. In this study, the relation of changes in cNOS and iNOS activities to LPO formation and NP-SH oxidation was examined in the gastric mucosa of rats with WIR stress. An increase in iNOS activity, but not a decrease in cNOS activity, correlated well with an increase in LPO concentration (r = 0.750) and NP-SH concentration (r = -0.808) in the gastric mucosa of rats with WIR stress. In addition, the above-mentioned changes in iNOS activity and LPO and NP-SH concentrations with lesion development in the gastric mucosa of rats with WIR stress were attenuated with both prevention of the lesion development and an increase in the concentration of gastric mucosal nitrite/nitrate, the breakdown products of NO, by pretreatment with aminoguanidine, a selective iNOS inhibitor. These results suggest that in the gastric mucosa of WIR-stressed rats, NO produced by increased iNOS could contribute to enhanced LPO formation and NP-SH oxidation, resulting in lesion development.