1. The interactions between nitric oxide (NO), prostacyclin and sensory neuropeptides in the maintenance of gastric mucosal integrity have been investigated in the anaesthetized rat. 2. Administration of either NG-monomethyl-L-arginine (L-NMMA) to inhibit endothelium-derived NO formation, indomethacin to inhibit prostanoid biosynthesis or chronic capsaicin pretreatment to deplete sensory neuropeptides, did not induce acute mucosal injury. 3. In capsaicin-pretreated rats, however, L-NMMA (12.5-100 mg kg-1 i.v.) dose-dependently induced acute mucosal damage, characterized as vasocongestion and haemorrhagic necrosis. The enatiomer D-NMMA (100 mg kg-1 i.v.) did not induce any detectable mucosal damage. 4. This mucosal injury induced by L-NMMA was inhibited by concurrent administration of L-arginine (300 mg kg-1 i.v.). 5. In indomethacin (5 mg kg-1 i.v.)-pretreated rats, L-NMMA also induced mucosal damage. Furthermore, following indomethacin administration in capsaicin-pretreated rats, L-NMMA induced widespread, severe haemorrhagic necrotic damage. 6. These findings suggest a role for endogenous NO formed from L-arginine, acting in concert with prostacyclin and sensory neuropeptides, in the modulation of gastric mucosal integrity.