An apical membrane Na(+)-H+ antiporter mediates proximal tubule NaCl and NaHCO3 reabsorption. The present studies examined whether chronic changes in dietary NaCl intake lead to an adaptation of the Na(+)-H+ antiporter. Rats were maintained either on a low-salt (LS, 0% NaCl) or a high-salt (HS, 2% NaCl) diet for 4 days. Na(+)-H+ antiporter was assayed using the acridine orange fluorescence method in apical membrane vesicles prepared by Mg2+ aggregation. Rats on LS diet exhibited a higher maximal activity (Vmax) for antiporter activity (0.109 +/- 0.008 s-1) compared with rats on HS diet (0.090 +/- 0.008 s-1; P less than 0.01), whereas Na activity (KNa) was similar (13.1 +/- 1.5 and 14.2 +/- 0.8 mM in HS and LS groups, respectively). The modulation of Na(+)-H+ antiporter activity was amiloride sensitive. Proton permeability, Na(+)-dependent [3H]glucose uptake, and vesicle enrichments were similar in both groups. In addition, the dietary protocols were not associated with any systemic acid-base disturbances, K+ deficiency, or hyperfiltration, conditions that have previously been demonstrated to alter Na(+)-H+ antiporter activity. Acute differences in extracellular fluid volume, induced by 10% body weight isohydric expansion failed to affect Na(+)-H+ antiporter activity. Thus chronic alterations in dietary NaCl intake alter the maximal activity (Vmax) of the Na(+)-H+ antiporter. This adaptation may contribute to decreased NaCl reabsorption in extracellular fluid volume expansion, enhanced NaCl reabsorption in extracellular fluid volume depletion, and enhanced NaHCO3 reabsorption in chronic metabolic alkalosis associated with volume contraction.