The effects of pretreatment with prostaglandin E2 (PGE2) on salicylate-induced gastric damage in the rat were studied with a gastric chamber model. Transmural potential difference (PD) and net potassium ion (K+) efflux were monitored as indices of gastric mucosal barrier integrity. Topical application of 20 mM salicylate for 10 min produced an abrupt drop in PD, an increase in net K+ flux, and the formation of hemorrhagic erosions covering approximately 24% of the glandular mucosa. Prior topical application of PGE2 at doses of 25, 75, and 300 micrograms/kg significantly reduced the extent of hemorrhagic erosions. However, PG pretreatment did not produce a reduction in the effects of topical salicylate on either PD or net K+ efflux. Rather, the drop in PD was initially accelerated and the net K+ efflux was increased by PGE2 pretreatment. Subsequently, in PGE2-pretreated mucosae, both parameters showed more rapid recovery toward control values. These results suggest that the mechanism of "cytoprotection" by PGE2 against salicylate-induced gastric damage is not a consequence of preservation of the gastric mucosal barrier.