We studied the control of processing of the epithelial Na+ channel (ENaC) through acute dietary Na loading and antidiuretic hormone. Acute salt repletion of Na-depleted rats decreased the abundance of fully processed ENaC proteins, assessed as the cleaved forms of α and γENaC and the mature glycosylated form of βENaC, within 2.5 h, despite sustained high levels of aldosterone in plasma. This phenomenon could not be explained by decreased aldosterone, increased Na+ delivery to the distal nephron, intracellular Na+ loading of ENaC-expressing cells, or decreased responsiveness of these cells to aldosterone. We found no evidence for the involvement of angiotensin II, atrial natriuretic peptide, or endothelin in the process. Administration of dDAVP to activate V2-type ADH receptors increased the abundance of cleaved γENaC and αENaC within 2 h. Unlike effects of aldosterone, dDAVP also increased the amount of full-length γENaC. Levels of mRNA for ENaC subunits were not raised under these conditions. We conclude that processing of ENaC subunits is modified acutely by aldosterone-independent processes, with Na+ loading inhibiting the rate of forward trafficking of assembled proteins and ADH stimulating subunit synthesis.