Regulation of the epithelial Na⁺ channel by aldosterone: Open questions and emerging answers. Aldosterone is the principal adrenal steroid controlling Na⁺ retention in amphibians and mammalians. It acts primarily by increasing the apical Na⁺ permeability through activation of the epithelial Na⁺ channel (ENaC). The cellular events mediating the hormonal action are mostly unknown. Early studies have provided evidence that the hormone functions to activate or translocate pre-existing channels by a yet undefined mechanism. In addition, enhanced de novo channel synthesis appears to take place as well. The molecular cloning of the three ENaC subunits has provided new powerful tools for testing and confirming this hypothesis, as well as for characterizing mechanisms by which ENaC is regulated. Another important development is the recent identification of several cDNAs corresponding to aldosterone-induced and suppressed mRNAs. The study of these genes and their putative interactions with ENaC is likely to provide important clues to the mechanisms by which aldosterone controls the apical Na⁺ permeability of tight epithelia. This article reviews recent developments in the field that may lead to the elucidation of the mechanisms by which the hormone controls Na⁺ transport.