To examine the effect of selective rise of plasma NaCl concentration (hypernatremia) on NaHCO3 reabsorption and associated NaCl reabsorption remaining during continuous ethacrynic acid infusion, hypertonic NaCl solution was infused in three groups of anesthetized volume-expanded dogs. In six dogs examined at constant hematocrit and plasma pH, bicarbonate and water reabsorptions were inversely related to PNa and reduced by 37% and 39% respectively by raising PNa from 140 to 200 mM. Chloride reabsorption remained essentially constant until PNa exceeded 170 to 180 mM. At PNa 200 mM, sodium reabsorption was reduced by 22 +/- 6%. In six other dogs, mechanical variations of GFR showed that the inhibitory effects of hypernatremia (PNa 199 +/- 3 mM) were less pronounced at low GFR. After subsequent administration of acetazolamide (30 mg/kg body wt), only 20% of control bicarbonate reabsorption remained and glomerulo-tubular balance was completely abolished. Both hypernatremia and acetazolamide inhibited NaHCO3 and NaCl reabsorption in a molar ratio of about 1:2, as in normonatremic dogs. Finally, experiments in six dogs showed that the inhibitory effects of hypernatremia (PNa 213 +/- 4 mM) were not altered by varying PCO2 and plasma pH. We conclude that hypernatremia inhibits paracellular water and NaCl reabsorption in the proximal tubules by reducing the osmotic force caused by transcellular NaHCO3 reabsorption. A rise in PNa does not stimulate transcellular NaCl reabsorption during distal inhibition by ethacrynic acid.