The natriuretic effect of calcium channel blockers has been attributed to hemodynamic changes and to poorly defined direct tubular effects. To test the possibility that verapamil may inhibit sodium reabsorption at the distal tubule, its effect on transepithelial sodium transport in aldosterone-stimulated A6 cells was determined. Cells were grown on permeable supports and short circuit current (Isc) measured in an Ussing chamber was used as surrogate marker for transepithelial sodium transport. Application of verapamil (300 µM) to the apical side inhibited Isc by 77% and was nearly as potent as 100 µM amiloride, which inhibited Isc by 87%. Verapamil-induced inhibition of Isc was accompanied by a significant increase in transepithelial resistance, suggesting blockade of an apical conductance. Its action on transepithelial sodium transport does not appear to occur through inhibition of L-type calcium channels since Isc was unaffected by removal of extracellular calcium. Furthermore, verapamil also does not appear to inhibit Isc by modulating intracellular Ca²⁺ stores since it fails to inhibit transepithelial sodium transport when added to the basolateral side. The effect on sodium transport is specific for verapamil since nifedipine, barium, 4 AP, and CTX do not significantly affect Isc. A direct effect of verapamil on the epithelial sodium channel was tested using oocytes injected with the alpha, beta, and gamma subunits. Verapamil (100 µM) inhibited more than 80% of the amiloride-sensitive whole cell current. In cell-attached oocyte membrane patches, the same dose of verapamil inhibited single ENaC channel activity by about 60%. We conclude that verapamil inhibits transepithelial sodium transport in A6 cells by blocking ENaC, and that the natriuresis observed with the administration of the verapamil may be due in part to its action on ENaC.