REGULATION OF GASTRIC-MUCOSAL INTEGRITY BY ENDOGENOUS NITRIC-OXIDE - INTERACTIONS WITH PROSTANOIDS AND SENSORY NEUROPEPTIDES IN THE RAT

The interactions between nitric oxide (NO), prostacyclin and sensory neuropeptides in the maintenance of gastric mucosal integrity have been investigated in the anaesthetized rat. Administration of either N(G)-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. 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 enantiomer D-NMMA (100 mg kg-1 i.v.) did not induce any detectable mucosal damage. This mucosal injury induced by L-NMMA was inhibited by concurrent administration of L-arginine (300 mg kg-1 i.v.). 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. 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.