1. Transmucosal electrical resistance (Rt) and short-circuit current (Isc) were determined in rabbit isolated fundic mucosa. Under basal conditions, with a HCO(3-)-free HEPES-buffered solution (pH 7.4) bathing both sides of the mucosae, Rt was 161.5 + 5.0 omega cm2 and Isc 41.8 +/- 1.8 microA cm-2, and these values were not significantly different to values observed in HCO(3-)-buffered Krebs-Hensleit solution. 2. The basal Isc was inhibited by the Cl- channel blocker diphenylamine-2-carboxylate, and ouabain, but unaffected by the Na+ channel blocker amiloride (10(-5) M), consistent with electrogenic chloride secretion dependent upon a sodium gradient. Prostaglandin E2 (10(-7) M) stimulated an increase in Isc which was susceptible to inhibition by diphenylamine-2-carboxylate, but not amiloride, again consistent with Cl- secretion. 3. Stepwise acidification of the mucosal solution to pH 2.8 resulted in an increase in Rt of 43%, as compared with that measured with mucosal pH 7.4. Isc did not change during the acidification to pH 2.8, indicating retention of tissue viability. Increased Rt while Isc remained constant is consistent with an acid-induced decrease in the shunt (paracellular) conductance in this Cl(-)-secreting tissue. At pH less than 2.8, Rt declined rapidly and Isc declined and reversed, consistent with H+ back-diffusion. Scanning electron microscopic investigation of tissue exposed to mucosal pH 2.8 revealed little difference from control (pH 7.4) tissue, but there was considerable evidence of cellular damage and membrane disruption in tissue exposed to pH 1.8. 4. Acidification of the serosal solution did not increase Rt, which was maintained until pH 3.7, and then rapidly declined at pH less than 3.7. Bilateral acidification produced a mixed response; Rt increased, as for mucosal acidification, down to pH 2.8, after which there was a rapid decline in Rt following the pattern observed for serosal acidification. 5. Compared at a mucosal pH approximately 2.8, DIDS (4 x 10(-4) M) and amiloride (10(-3) M) inhibited the acid-induced increase in Rt, suggesting a role for both Cl(-)-HCO3- and Na(+)-H+ exchange in the response. In contrast, the acid-induced increase in Rt was unaffected by a lower concentration of amiloride (10(-5) M), acetazolamide and ouabain. Therefore, neither Na+ channels nor a Na+ gradient appear to be involved in the acid-induced increase in Rt.(ABSTRACT TRUNCATED AT 400 WORDS)