Alendronate, an aminobisphosphonate, produces as a side effect a topical (pill-induced) esophagitis. To gain insight into this phenomenon, we assessed the effects of luminal alendronate on both esophageal epithelial structure and function. Methods: Sections of rabbit esophageal epithelium were exposed to luminal alendronate at neutral or acidic pH while mounted in Ussing chambers to monitor transmural electrical potential difference (PD), short circuit current (I_sc) and resistance (R). Morphologic changes were sought by light microscopy on hematoxylin & eosin stained sections. Impedance analysis was used for localization of alendronate-induced effects on ion transport. Results: Luminal, but not serosal, alendronate, (pH 6.9-7.2), increased PD and I_sc in a dose and time-dependent manner, with little change in R and mild edema of surface cell layers. The changes in I_sc (and PD) were reversible with drug washout and could be prevented either by inhibition of Na,K-ATPase activity with serosal ouabain or by inhibition of apical Na channels with luminal acidification to pH 2.0 with HCl. An effect on apical Na channel activity was also supported by impedance analysis. Luminal alendronate at acidic pH was more damaging than either alendronate at neutral pH or acidic pH alone. These data suggest that alendronate stimulates net ion (Na) transport in esophageal epithelium by increasing apical membrane sodium channel activity and that this occurs with limited morphologic change and no alteration in barrier function. Also alendronate is far more damaging at acidic than at neutral pH suggesting its association with esophagitis requires gastric acid for expression. This expression may occur either by potentiation between the damaging effects of (refluxed) gastric acid and drug or by acid-induced conversion of the drug to a more toxic form.