NaCl administration enhances HCO3 secretion in the distal tubule of animals with chronic metabolic alkalosis but does not correct the augmented H+ secretion characteristic of this disorder. The present studies used in vivo microperfusion micropuncture to investigate whether combined repletion of K+ and Cl- corrected the augmented H+ secretion in the distal tubule of rats with chronic furosemide-induced metabolic alkalosis. Correction of alkalosis was induced in one group of animals with NaCl and in another group with a similar amount of Cl- as NaCl + KCl for 24 h; each group was compared with animals with maintained alkalosis. Total 24-h urine HCO3 excretion by each Cl(-)-repleted group comprised > or = 70% of the calculated HCO3 loss necessary to induce the respective decrease in plasma total CO2. Alkalotic animals given NaCl+KCl had significantly lower H+ secretion in the distal tubule compared with animals with maintained alkalosis (15.5 +/- 1.2 vs. 34.6 +/- 1.8 pmol.mm-1.min-1, P < 0.01) but those given only NaCl did not (28.3 +/- 1.5 pmol.mm-1.min-1, P = 0.14). H+ secretion was not different among control animals given similar amounts of Na+, K+, and Cl-. These studies demonstrate that Cl- repletion corrects chronic furosemide-induced metabolic alkalosis predominantly by a renal mechanism and that combined administration of K+ and Cl-, but not of Cl- alone, corrects the augmented H+ secretion in the distal tubule in this model of chronic alkalosis.