The natriuretic effect of Ca²⁺ channel blockers has been attributed to hemodynamic changes and to poorly defined direct tubular effects. To test the possibility that verapamil may inhibit Na⁺ reabsorption at the distal tubule, its effect on transepithelial Na⁺ transport in aldosterone-stimulated A6 cells was determined. Cells were grown on permeable supports, and short-circuit current (I_sc) measured in an Ussing chamber was used as a surrogate marker for transepithelial Na⁺ transport. Application of 300 µM verapamil to the apical side inhibited I_sc by 77% and was nearly as potent as 100 µM amiloride, which inhibited I_sc by 87%. Verapamil-induced inhibition of I_sc was accompanied by a significant increase in transepithelial resistance, suggesting blockade of an apical conductance. Its action on transepithelial Na⁺ transport does not appear to occur through inhibition of L-type Ca²⁺ channels, since I_sc was unaffected by removal of extracellular Ca²⁺. Verapamil also does not appear to inhibit I_sc by modulating intracellular Ca²⁺ stores, since it fails to inhibit transepithelial Na⁺ transport when added to the basolateral side. The effect on Na⁺ transport is specific for verapamil, since nifedipine, Ba²⁺, 4-aminopyridine, and charybdotoxin do not significantly affect I_sc. A direct effect of verapamil on the epithelial Na⁺ channel (ENaC) was tested using oocytes injected with the -, -, and -subunits. We conclude that verapamil inhibits transepithelial Na⁺ transport in A6 cells by blocking ENaC and that the natriuresis observed with administration of verapamil may be due in part to its action on ENaC.