The protective effects of the proton pump inhibitor lansoprazole on gastric mucosal damage induced by ethanol-HCl or hemorrhagic shock were investigated in the present study. The morphometric analysis of gastric histological sections revealed that lansoprazole dose-dependently reduced mucosal injury evoked by ethanol-HCl (ED50 = 24.3 micromol/kg) or hemorrhagic shock (ED50 = 38.9 micromol/kg), these effects being associated with marked increments of Alcian blue recovery from gastric bound mucus (ED50 = 31.4 micromol/kg and 27.6 micromol/kg, respectively). In addition, lansoprazole inhibited gastric acid secretion from pylorus-ligated rats (ED50 = 9.8 micromol/kg). Further experiments, performed on rats with ethanol-HCl-induced gastric injury, indicated that the protective effects of lansoprazole were not modified by L-365,260, suramin, N(G)-nitro-L-arginine, or systemic ablation of capsaicin-sensitive sensory nerves, whereas they were partly blocked by indomethacin and fully prevented by N-ethyl-maleimide. In addition, lansoprazole did not modify somatostatin concentrations in gastric mucosa. The present results provide evidence that lansoprazole prevents the necrotic damage of gastric mucosa induced by ethanol-HCl or hemorrhagic shock. According to the rank order of ED50 values, these effects appear to depend mainly on the enhancement of the gastric mucus barrier rather than on the reduction of acid secretion. It is also proposed that an increased production of prostaglandins, as well as an increased availability of sulfhydryl compounds at level of gastric mucosa may account for the gastroprotective effects of lansoprazole.