The current model of duodenal HCO₃⁻ secretion proposes that basal secretion results from Cl⁻/HCO₃⁻ exchange, whereas cyclic adenosine monophosphate (cAMP)-stimulated secretion depends on a cystic fibrosis transmembrane conductance regulator channel (Cftr)-mediated HCO₃⁻ conductance. However, discrepancies in applying the model suggest that Cl⁻/HCO₃⁻ exchange also contributes to cAMP-stimulated secretion. Of 2 candidate Cl⁻/HCO₃⁻ exchangers, studies of putative anion transporter-1 knockout (KO) mice find little contribution of putative anion transporter-1 to basal or cAMP-stimulated secretion. Therefore, the role of down-regulated in adenoma (Dra) in duodenal HCO₃⁻ secretion was investigated using DraKO mice.

Duodenal HCO₃⁻ secretion was measured by pH stat in Ussing chambers. Apical membrane Cl⁻/HCO₃⁻ exchange was measured by microfluorometry of intracellular pH in intact villous epithelium. Dra expression was assessed by immunofluorescence.

Basal HCO₃⁻ secretion was reduced ∼55%–60% in the DraKO duodenum. cAMP-stimulated HCO₃⁻ secretion was reduced ∼50%, but short-circuit current was unchanged, indicating normal Cftr activity. Microfluorimetry of villi demonstrated that Dra is the dominant Cl⁻/HCO₃⁻ exchanger in the lower villous epithelium. Dra expression increased from villous tip to crypt. DraKO and wild-type villi also demonstrated regulation of apical Na⁺/H⁺ exchange by Cftr-dependent cell shrinkage during luminal Cl⁻ substitution.

In murine duodenum, Dra Cl⁻/HCO₃⁻ exchange is concentrated in the lower crypt-villus axis where it is subject to Cftr regulation. Dra activity contributes most basal HCO₃⁻ secretion and ∼50% of cAMP-stimulated HCO₃⁻ secretion. Dra Cl⁻/HCO₃⁻ exchange should be considered in efforts to normalize HCO₃⁻ secretion in duodenal disorders such as ulcer disease and cystic fibrosis.