AIM To examine the effect of irsogladine, a novel antiulcer drug, on the mucosal ulcerogenic response to monochloramine (NH 2Cl) in rat stomach, in comparison with rebamipide, another antiulcer drug with cytoprotective activity. METHODS AND RESULTS Oral administration of NH 2Cl (120*!mM) produced severe hemorrhagic lesions in unanesthetized rat stomachs. Both irsogladine ( 1*!mg/*!kg - 10*!mg/*!kg , po ) and rebamipide ( 30*!mg/*!kg - 100*!mg/*!kg , po ) dose dependently prevented the development of these lesions in response to NH 2Cl, the effect of irsogladine was significant at 3*!mg/*!kg or greater, and that of rebamipide only at 100*!mg/*!kg . The protective effect of irsogladine on NH 2Cl induced gastric lesions was significantly reduced by N G nitro L arginine methyl ester (L NAME) but not by indomethacin, while that of rebamipide was significantly mitigated by indomethacin but not by L NAME. Topical application of NH 2Cl (20*!mM) caused a marked reduction of potential difference (PD) in ex vivo stomachs. This PD reduction was not affected by mucosal application of irsogladine, but significantly prevented by rebamipide. The mucosal exposure to NH 4OH (120*!mM) also caused a marked PD reduction in the ischemic stomach (bleeding from the carotid artery), resulting in gastric lesions. These ulcerogenic and PD responses caused by NH 4OH plus ischemia were also significantly mitigated by rebamipide, in an indomethacin sensitive manner, while irsogladine potently prevented such lesions without affecting the PD response, in a L NAME sensitive manner. CONCLUSION These results suggest that ① NH 2Cl generated either exogenously or endogenously damages the gastric mucosa, ② both irsogladine and rebamipide protect the stomach against injury caused by NH 2Cl, and ③ the mechanism underlying the protective action of irsogladine is partly mediated by endogenous nitric oxide, while that of rebamipide is in part mediated by endogenous prostaglandins. AIM To examine the effect of irsogladine, a novel antiulcer drug, on the mucosal ulcerogenic response to monochloramine (NH 2 Cl) in rat stomach, in comparison with rebamipide, another antiulcer drug with cytoprotective activity. METHODS AND RESULTS Oral administration of NH 2 Cl (120 *! mM) produced severe hemorrhagic lesions in unanesthetized rat stomachs. Both irsogladine (1 *! mg / *! kg - 10 *! mg / *! kg, po) and rebamipide (30 * ! mg / *! kg, po) dose dependently prevented the development of these lesions in response to NH 2 Cl, the effect of irsogladine was significant at 3 *! mg / *! kg or greater, and that of rebamipide only at 100 *! mg / *! kg. The protective effect of irsogladine on NH 2Cl induced gastric lesions was significantly reduced by NG nitro L arginine methyl ester (L NAME) but not by indomethacin, while that of rebamipide was significantly mitigated by indomethacin but not by L NAME Topical application of NH 2 Cl (20 *! MM) caus This PD reduction was not affected by mucosal application of irsogladine, but particularly prevented by rebamipide. The mucosal exposure to NH 4 OH (120 *! mM) also caused a marked PD reduction in the ischemic stomach (bleeding from the carotid artery), resulting in gastric lesions. These ulcerogenic and PD responses caused by NH 4OH plus ischemia were also significantly mitigated by rebamipide, in an indomethacin sensitive manner, while irsogladine potently attended to lesions without affecting the PD response, in a L NAME sensitive manner. CONCLUSION These results suggest that ① NH 2 Cl generated either exogenously or endogenously damages the gastric mucosa, ② both irsogladine and rebamipide protect the stomach to injury caused by NH 2Cl, and ③ the mechanism underlying the protective action of irsogladine is partly mediated by endogenous nitric oxide, while that of rebamipide is in pa rt mediated by endogenous prostaglandins.