Heavy alcohol consumption is associated with the development of reflux esophagitis. Among the reasons for this are impairment of the antireflux barrier, stimulation of acid secretion, and altered tissue resistance. To explore the contribution of altered tissue resistance to the development of esophagitis, sections of rabbit esophageal epithelium were mounted in Ussing chambers and exposed luminally to 10% ethanol, acid (HCl, pH 2), or combinations of both. Tissue injury was assessed by measurements of potential difference (PD), short circuit current (I-sc) and electrical resistance (R) and by histology. Tissues exposed luminally to HCl for 1 hr exhibited little or no change electrically or morphologically compared to Ringer controls, while luminal exposure to 10% ethanol for 1 hr lowered PD (53 +/- 4%), I-sc (30 +/- 1%), and R (31 +/- 5%) and produced cellular edema in the upper layers. Simultaneous exposure to ethanol and acid resulted in significantly greater declines in PD (81 +/- 1%) and I-sc (70 +/- 2%), but not R (40 +/- 4%), and greater morphologic damage. Moreover, this vulnerability of ethanol-exposed tissues to acid was demonstrable at generally innocuous levels of acidity (pH 2-4), after only short periods of ethanol exposure (10 min) and with delays for acid exposures of up to 1 hr following ethanol removal from the bathing solution. In conclusion, ethanol has a direct noxious effect on esophageal epithelium, which predisposes the tissue to acid injury. Tissue vulnerability develops with even short exposures to clinically relevant concentrations of ethanol, lasts for at least 1 hr after ethanol clearance, and transforms relatively innocuous concentrations of acid into damaging agents. These results support the likelihood that ethanol's ability to alter tissue resistance plays an important role in the development of reflux esophagitis in humans.