Concentrated ethanol causes gastric lesions by a mechanism that is poorly understood. We have investigated this mechanism in the rat stomach via gross morphologic, videomicroscopic, histochemical, and pharmacologic approaches. Within 1 min of contact, ethanol caused diffuse mucosal hyperemia. By 5 min, hyperemia greatly intensified at some mucosal sites. Beneath sites where mucosal hyperemia developed, intramural venules strongly constricted at 3-13 s postethanol, whereas submucosal arterioles dilated more than two times in diameter by 25 s. Submucosal venular constriction began sooner than arteriolar dilation (9 vs. 16 s, p less than 0.05). One-third of the gastric mucosal mast cells degranulated by 15 s postethanol; 50% discharged by 30 s. Ethanol-induced hyperemia was markedly reduced by lipoxygenase-selective inhibitors BW755C or nordihydroguaiaretic acid, or by the H1-antihistamine pyrilamine, but not by indomethacin, cimetidine, phentolamine, or methysergide. Based on these results, a model for the pathogenesis of ethanol-induced gastric lesions is proposed.