Exposure of the rat stomach to acetic acid (0.3-3%) caused a concentration-dependent reduction of transmucosal potential difference (PD) and increase of luminal pH (gastric alkaline response). These concentrations of acetic acid, when given topically to the stomach, significantly prevented development of gastric lesions induced by subsequent exposure to absolute ethanol, the inhibition being 42.3%, 95.8% and 70.4% at concentrations of 0.3%, 1% and 3%, respectively. Gastric alkaline response and protection of ethanol-induced gastric lesions caused by 1% acetic acid were significantly attenuated by pretreatment of the animals with indomethacin (5 mg/kg, s.c.). Although other related carboxylic acids at 1% concentration such as citric acid (52 mM), maleic acid (86 mM) and formic acid (217 mM) affected both PD and luminal pH in varying degrees, these agents, except for 1% maleic acid, failed to prevent gastric lesions in response to absolute ethanol. Similar to 1% acetic acid (167 mM), gastric alkaline response and adaptive cytoprotection induced by 1% maleic acid were significantly antagonized by pretreatment with indomethacin. Formic acid also induced a significant gastric alkaline response, but this effect was not effected by indomethacin. These results suggest that dilute acetic acid such as vinegar (approximately 3% acetic acid) acts as a mild irritant to the stomach, and induces alkaline response and adaptive cytoprotection, mediated by endogenous prostaglandins. Other related carboxylic acids may have similar effects, but those depend upon the concentrations used.