Pancreatic ductal epithelium produces a HCO₃⁻-rich fluid. HCO₃⁻ transport across ductal apical membranes has been proposed to be mediated by both SLC26-mediated Cl⁻/HCO₃⁻ exchange and CFTR-mediated HCO₃⁻ conductance, with proportional contributions determined in part by axial changes in gene expression and luminal anion composition. In this study we investigated the characteristics of apical Cl⁻/HCO₃⁻ exchange and its functional interaction with Cftr activity in isolated interlobular ducts of guinea pig pancreas. BCECF-loaded epithelial cells of luminally microperfused ducts were alkalinized by acetate prepulse or by luminal Cl⁻ removal in the presence of HCO₃⁻-CO₂. Intracellular pH recovery upon luminal Cl⁻ restoration (nominal Cl⁻/HCO₃⁻ exchange) in cAMP-stimulated ducts was largely inhibited by luminal dihydro-DIDS (H₂DIDS), accelerated by luminal CFTR inhibitor inh-172 (CFTRinh-172), and was insensitive to elevated bath K⁺ concentration. Luminal introduction of CFTRinh-172 into sealed duct lumens containing BCECF-dextran in HCO₃⁻-free, Cl⁻-rich solution enhanced cAMP-stimulated HCO₃⁻ secretion, as calculated from changes in luminal pH and volume. Luminal Cl⁻ removal produced, after a transient small depolarization, sustained cell hyperpolarization of ∼15 mV consistent with electrogenic Cl⁻/HCO₃⁻ exchange. The hyperpolarization was inhibited by H₂DIDS and potentiated by CFTRinh-172. Interlobular ducts expressed mRNAs encoding CFTR, Slc26a6, and Slc26a3, as detected by RT-PCR. Thus Cl⁻-dependent apical HCO₃⁻ secretion in pancreatic duct is mediated predominantly by an Slc26a6-like Cl⁻/HCO₃⁻ exchanger and is accelerated by inhibition of CFTR. This study demonstrates functional coupling between Cftr and Slc26a6-like Cl⁻/HCO₃⁻ exchange activity in apical membrane of guinea pig pancreatic interlobular duct.

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