To test for a defect in HCO3− handling, AC6loxloxPax8Cre mice and AC6loxlox were followed for 3 days during baseline conditions and subsequently challenged with HCO3− (NaHCO3) loading for 7 days (supplied via drinking water). Because daily water intake is double in AC6loxloxPax8Cre mice, NaHCO3 was supplied to this genotype at a 50% lower concentration compared with WT mice (0.14 M in AC6loxloxPax8Cre mice compared with 0.28 M in AC6loxlox mice). (A) Fluid intake during baseline conditions and during HCO3− loading (n=8 per genotype). (B) Urinary pH during baseline conditions and during HCO3− challenge (n=8/genotype). (C,D) Blood pH and HCO3− concentrations under baseline conditions and after 7 days HCO3− challenge (n=8/genotype). Statistical comparisons in (A and B): *AC6loxloxPax8Cre compared with AC6loxlox mice (P<0.05); #baseline mean compared with HCO3− challenge in both genotypes (P<0.05). Statistical comparisons in (C,D): *compared with AC6loxlox mice or baseline (P<0.05). Statistical comparisons on left and right side of dashed line in (A, B) were performed separately using two-way repeated measurement ANOVAs. Values indicate mean ± S.E.M. Values on bars indicate sample size. Abbreviation: Base, Baseline.