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¹ Human Nutrition and ² Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
³ Faculty of Life Sciences, University of Manchester, Manchester M13 9NT, England, UK

Correspondence to Hiroshi Ishiguro: ishiguro{at}htc.nagoya-u.ac.jp

Pancreatic duct epithelium secretes a HCO₃^–-rich fluid by a mechanism dependent on cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane. However, the exact role of CFTR remains unclear. One possibility is that the HCO₃^– permeability of CFTR provides a pathway for apical HCO₃^– efflux during maximal secretion. We have therefore attempted to measure electrodiffusive fluxes of HCO₃^– induced by changes in membrane potential across the apical membrane of interlobular ducts isolated from the guinea pig pancreas. This was done by recording the changes in intracellular pH (pH_i) that occurred in luminally perfused ducts when membrane potential was altered by manipulation of bath K⁺ concentration. Apical HCO₃^– fluxes activated by cyclic AMP were independent of Cl^– and luminal Na⁺, and substantially inhibited by the CFTR blocker, CFTR_inh-172. Furthermore, comparable HCO₃^– fluxes observed in ducts isolated from wild-type mice were absent in ducts from cystic fibrosis (F) mice. To estimate the HCO₃^– permeability of the apical membrane under physiological conditions, guinea pig ducts were luminally perfused with a solution containing 125 mM HCO₃^– and 24 mM Cl^– in the presence of 5% CO₂. From the changes in pH_i, membrane potential, and buffering capacity, the flux and electrochemical gradient of HCO₃^– across the apical membrane were determined and used to calculate the HCO₃^– permeability. Our estimate of 0.1 µm sec^–1 for the apical HCO₃^– permeability of guinea pig duct cells under these conditions is close to the value required to account for observed rates of HCO₃^– secretion. This suggests that CFTR functions as a HCO₃^– channel in pancreatic duct cells, and that it provides a significant pathway for HCO₃^– transport across the apical membrane.

© 2009 Ishiguro et al.
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