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Mineralocorticoids play a major role in the regulation of sodium transport in a variety of tissues, including the cortical collecting duct (CCD) of the mammalian nephron. To assess, in part, the underlying mechanism(s) of this control, the present studies were designed to evaluate, first, the influence of mineralocorticoids on the Na-K-ATPase activity in the rabbit CCD and, secondly, a possible role of sodium entry into the cell at the luminal border on the regulation of the Na-K-ATPase. In the first series of studies, rabbits were maintained on a low sodium diet which raised serum aldosterone levels from 16 to 70 ng/dl after 3-4 days, with further elevations being expressed with treatment for two weeks or more. In CCDs isolated from these animals, the Na-K-ATPase increased from 13 to 40 pmol ADP min-1 mm-1 after 3-4 days on the low sodium regimen, but then declined, returning to control values after approximately 2 weeks. This decline in activity was preceded by a decrease in the Na+ concentration of the urine to low levels and hence, likely coincided with a decreased delivery of sodium to, and sodium entry into the cells of, the CCD. If dietary manipulations were used to maintain a high delivery of sodium to the CCD in the animal, elevation of plasma mineralocorticoid levels by treatment with deoxycorticosterone acetate (DOCA) caused a similar elevation in the Na-K-ATPase activity after 3-4 days, which did not decline with continued treatment for up to 2 weeks. Furthermore, it was observed that mineralocorticoids only exerted their effect on the Na-K-ATPase after a latent period of 1 day, well after sodium excretion had fallen, indicating that sodium entry into the CCD cells was already stimulated. If animals were simultaneously treated with DOCA and the sodium channel blocker amiloride for 3-4 days, the effects on the Na-K-ATPase were markedly reduced, whereas amiloride treatment alone had no effect on the enzyme activity. Since others have shown that mineralocorticoids induce synthesis of the Na-K-ATPase subunits in toad bladder cells in an amiloride-insensitive manner, sodium must be exerting its effect on a process after translation. It is concluded that the initial effect of mineralocorticoids in the CCD is on sodium entry with a delayed induction of the Na-K-ATPase, which is regulated by Na-dependent modulation of a posttranslational process.