A B S T R A C T To increase our understanding of the pathophysiology of reflux esophagitis, we sought the early sequence of changes in mucosal structure and function in acutely acid-damaged rabbit esophagus. Using a perfused catheter technique esophageal potential difference (PD) profiles were obtained in anesthetized rabbits before, during, and after perfusion of the lower one-half of the esophagus with phosphatebuffered saline or 80 mM HCI-80 mM NaCl. When acid perfusion reduced the lower esophageal PD by 40-50% or 80-100% of the initial values, the esophagus was removed, sectioned, and the mucosa studied with light microscopy, transmission electron microscopy, and Ussing chamber technique for evaluation of sodium and mannitol transport. The earlier stage of acid damage (PD 140-50%) was associated with reduced mucosal resistance from 2,180±+199 to 673±+157 ohm * cm2 and increased passive transport of sodium (0.10+0.06 to 1.82 +0.48 geq/h .cm2) and mannitol (0.008+0.003 to 0.051±0.012 MM/h -cm2) (P < 0.05).There was no significant change in short circuit current (0.35±0.05 to 0.35±0.04) or net sodium transport (0.32±0.06 to 0.37±0.12) at this stage, and the only morphologic finding was dilated intercellular spaces on electron microscopy. The later stage ofacid damage (PDJ80-100%) exhibited a further reduction in resistance to 299±65 ohm cm2 (P < 0.05), a finding now accompanied by a reduction in short circuit current (0.35±0.05 to 0.21±0.04 Aeq/h -cm2) and complete inhibition of net sodium transport (0.32±0.06 to 0.01 ±0.13) (P < 0.05). Morphologic studies at this time revealed cellular necrosis, edema, and vesicle formation in the stratum spinosum. Both gross mucosal changes and transmural necrosis were notably absent. When esophageal perfusion was performed with a combination of acid (80 mM HCG-80 mM NaCl) and pepsin (100 ,ug/ml), the morphologic and physiologic findings were essentially the same as with acid alone; however, the time of perfusion to reach either the 50 or 100%