This study was conducted to determine whether a chronic increase in sodium delivery to, and sodium uptake by, the distal tubule stimulates the transport capacity of this tubular segment. To increase the rate of sodium delivery to the distal tubule, furosemide (12 mg/day) was administered continuously to rats by osmotic minipump for 6 days. Volume depletion was prevented by giving the animals a drinking solution containing 0.8% NaCl and 0.1% KCl. Control animals were given vehicle (0.9% NaCl) by osmotic minipump and tap water to drink. All animals were adrenalectomized and given replacement doses of aldosterone (0.5 microgram.100 g-1.day-1) and dexamethasone (1.2 microgram.100 g-1.day-1) to eliminate changes in adrenal corticosteroid levels. Furosemide was withdrawn 12 h before sodium and potassium transport rates were measured in distal tubules by in vivo microperfusion. We found that increased sodium uptake dramatically enhanced the transport capacity of the distal tubule. Sodium absorption rose from 71.7 to 316.7 pmol.min-1.mm-1, and potassium secretion increased from 30.7 to 73.7 pmol.min-1.mm-1. This response was accompanied by an increase in cell and mitochondrial volume and by proliferation of the basolateral membrane of distal convoluted cells, connecting tubule cells, and principal cells in the distal tubule. We conclude that a chronic increase in sodium uptake by the distal tubule, independent of alterations in extracellular fluid volume and aldosterone levels, stimulates the transport capacity of this nephron segment in part by inducing specific alterations in cell ultrastructure.