Activation of the CFTR Cl(-) channel inhibits epithelial Na(+) absorption, according to studies on native epithelia derived from airways, colon and kidney, and can also be demonstrated in overexpressing cells. However, Na(+) absorption is not inhibited by CFTR in the native sweat duct epithelium. The mechanism for the inhibition of epithelial sodium channels (ENaC) has been examined in most detail in Xenopus oocytes coexpressing CFTR and ENaC. It was shown that ENaC is inhibited during stimulation of CFTR in Xenopus oocytes, independent of the experimental setup and the magnitude of the whole-cell current. However, a minimal Cl(-) conductance is required for inhibition of ENaC, and inhibition is augmented at higher CFTR-to-ENaC currents ratios. Low-CFTR-to-ENaC conductance ratios may be the reason for the absence of ENaC inhibition, as described recently. Similar to CFTR, ClC-0 Cl(-) currents also inhibit ENaC, as well as high extracellular Na(+) and Cl(-) in partially permeabilized oocytes. Thus, inhibition of ENaC is not specific to CFTR and could be mediated by Cl(-) flow and/or changes in the intracellular Cl(-) concentration. These results are reminiscent of the Cl(-) feedback regulation observed in mouse mandibular duct cells. Current results obtained with ENaC mutants examined in Xenopus oocytes suggest a charge interaction of Cl(-) ions with the epithelial sodium channel.