Although nitric oxide (NO) has been known to play important roles in various biological events, the pathophysiological role of NO in the stomach remains to be elucidated. Since endotoxin induces NO synthase (NOS) in various tissues, the effect of lipopolysaccharide (LPS) on the stomach was studied in rats which were given water-immersion-restraint (WIR) stress. WIR treatment significantly increased the vascular permeability of gastric mucosa and induced mucosal injury. When LPS was injected intravenously to the rat, inducible-type NOS (iNOS) markedly increased in the gastric smooth muscular layer without affecting levels of brain-type isozyme (bNOS). LPS also increased gastric mucosal blood flow but suppressed the secretion of gastric acid. NG-(1-iminoethyl)-L-ornithine (NIO), a potent inhibitor of NOS, completely inhibited the LPS-induced increase in mucosal blood flow without affecting the acid secretion in control and LPS-treated rats. LPS markedly suppressed the WIR-induced mucosal injury by some NIO-inhibitable mechanism. These findings suggested that NO derived from gastric iNOS might play important roles in the suppression of stress-induced mucosal injury of the stomach.