Gastric ulcerations were produced in rats by oral administration of aspirin (ASA) suspended in a vehicle consisting of either water or increasing concentrations of HCl (0.005 M to 0.35 M). The lesions were prevented by antisecretory doses of a histamine H2 blocker (cimetidine) and by an anticholinergic agent (pro-banthine), but only when the acidity of the vehicle was low (0.05 M to 0.15 M), not at higher (0.35 M). On the other hand, 16,16-dimethyl PGE2 prevented ulcer formation even when ASA was suspended in all HCl concentrations, including 0.35 M HCl. In other studies, gastric mucosal necrosis was produced by oral administration of absolute ethanol. These lesions were not affected by cimetidine or two anticholinergic agents, pro-banthine and methscopolamine bromide, nor by alkalinization of the gastric lumen with NaHCO3 or pH 7 buffer; however, these ethanol-induced lesions were completely prevented by 16,16-dimethyl PGE2. We conclude that antisecretory agents, by blocking endogenous formation of acid, are antiulcer as long as no acid or only small amounts of acid (1 ml of 0.15 M or less) are given together with ASA. When higher concentrations are used (e.g. 0.35 M HCl), the antisecretory effect of the inhibitors is overcome by the exogenous acid, and ulcers still form. Under these conditions, only "true" cytoprotective agents, such as 16,16-dimethyl PGE2, prevent ASA-induced ulcers, even in the presence of high acidity. Although cimetidine and pro-banthine were shown earlier to reduce ASA-induced ulcers at nonantisecretory doses, these agents may still decrease acid formation within the gastric glands.(ABSTRACT TRUNCATED AT 250 WORDS)