In vitro microperfusion experiments were performed to determine whether chronic metabolic acidosis or chronic alterations in sodium intake cause adaptive changes in bicarbonate or ammonium transport in the medullary thick ascending limb (MTAL) of the rat. In all experiments, MTAL were studied under standard conditions in vitro with 25 mM bicarbonate in perfusate and bath. Thus changes in transport rates reflect adaptive changes in the intrinsic transport properties of the tubule cells. Chronic metabolic acidosis (induced by oral NH4Cl loading) increased MTAL bicarbonate absorption by 53% and increased net ammonium absorption by 36%. Chronic administration of NaHCO3 (0.28 M NaHCO3 drinking H2O) increased MTAL bicarbonate absorption by 50% and increased net ammonium absorption by 54%, despite systemic metabolic alkalosis. Chronic administration of NaCl (0.28 M NaCl drinking H2O) also increased bicarbonate absorption by 50%. Thus an increase in sodium intake stimulated bicarbonate absorptive capacity to a similar extent when sodium was administered with either chloride or bicarbonate. Moderate dietary sodium restriction (0.5% NaCl) reduced bicarbonate absorption by 20% compared with pair-fed sodium-replete controls (2.2% NaCl). These results demonstrate that 1) the MTAL is a site of regulation of renal acid-base transport, 2) chronic metabolic acidosis is associated with adaptive increases in MTAL bicarbonate and ammonium absorption, changes that are appropriate to correct the acidosis, and 3) dietary sodium intake is an important determinant of MTAL bicarbonate and ammonium transport capacity. The response of the MTAL to changes in sodium intake suggests that this segment may play an important role in maintaining acid-base balance when NaCl intake is altered.