We found that the gastric mucosal lesion induced by 60% ethanol containing 150 mM HCl was reduced by pre-loading the rat with restraint and water-immersion stress (22 degrees C). The resistance to ethanol injury was maximal in 1-hr stress loaded rats and gradually decreased with increasing time of stress (2-6 hr). The protective effect of stress was markedly decreased by subdiaphragmatic truncal vagotomy, and electrical stimulation of vagal nerves afforded similar protection as observed after stress. In contrast, pretreatment with atropine markedly reduced ethanol injury in both the control and 1 hr stress-loaded rats. One-hour stress produced surface epithelial cell damage in sham vagotomized rats, but the surface cells were almost intact in vagotomized rats. Pretreatment with indomethacin significantly mitigated the protective effect of stress against ethanol injury. However, the level of mucosal prostaglandin E2 was not changed 1 hr after stress, and it tended to decrease 6 hr after stress. Pretreatments with 1-hr stress and vagal stimulation weakly reduced localized staining of gastric mucosa with gentian violet. We conclude that adaptive protection can be achieved by restraint and water-immersion stress.