To examine the exact target cell and mechanism of action of epidermal growth factor (EGF) in the isolated cortical collecting duct from rabbit kidney, we compared electrical properties of collecting duct (CD) cells (principal cells) and intercalated (IC) cells in absence and presence of EGF at 10(-8) M. Differentiation of CD and IC cells was based on values of basolateral membrane voltage (Vb) and fractional apical membrane resistance (fRa). In CD cells, upon addition of EGF to bath, lumen-negative transepithelial voltage (VT) was decreased from -8.0 +/- 1.9 to -2.4 +/- 1.3 mV (n = 22, P less than 0.001), but Vb was little changed (from -85.1 +/- 2.8 to -83.1 +/- 2.7 mV, n = 19), indicating that EGF in bath mainly caused changes in apical membrane voltage. In addition, peritubular EGF increased transepithelial resistance (RT) from 132.9 +/- 15.8 to 153.8 +/- 18.4 omega.cm2 (n = 16, P less than 0.001) as well as fRa from 0.31 +/- 0.06 to 0.39 +/- 0.07 (n = 12, P less than 0.01). These actions of EGF were prevented by pretreatment with 50 microM luminal amiloride. Luminal EGF had no effects on VT, Vb, RT, or fRa of CD cells. In IC cells, upon addition of EGF to bath, neither Vb nor fRa was affected. From these results, we conclude that EGF acts on the CD cell at the basolateral border and inhibits mainly the amiloride-sensitive Na+ conductance in the apical membrane.