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Am J Physiol Gastrointest Liver Physiol 274: G718-G726, 1998;
0193-1857/98 $5.00
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Vol. 274, Issue 4, G718-G726, April 1998

Dual role of CFTR in cAMP-stimulated HCO<SUP>−</SUP><SUB>3</SUB> secretion across murine duodenum

Lane L. Clarke and Matthew C. Harline

Dalton Cardiovascular Research Center and Department of Veterinary Biomedical Sciences, University of Missouri-Columbia, Columbia, Missouri 65211

The role of the cystic fibrosis transmembrane conductance regulator (CFTR) in cAMP-stimulated HCO<SUP>−</SUP><SUB>3</SUB> secretion across the murine duodenum was investigated. Serosal-to-mucosal flux of HCO<SUP>−</SUP><SUB>3</SUB> (Jsright-arrow m, in µeq · cm-2 · h-1) and short-circuit current (Isc; in µeq · cm-2 · h-1) were measured by the pH stat method in duodenum from CFTR knockout [CFTR(-)] and normal [CFTR(+)] mice. Under control conditions, forskolin increased Jsright-arrow m and Isc (+1.7 and +3.5, respectively) across the CFTR(+) but not CFTR(-) duodenum. Both the forskolin-stimulated Delta Jsright-arrow m and Delta Isc were abolished by the CFTR channel blocker 5-nitro-2-(3-phenylpropylamino)benzoate, whereas inhibition of luminal Cl-/ HCO<SUP>−</SUP><SUB>3</SUB> exchange by luminal Cl- removal or DIDS reduced the Jsright-arrow m by ~18% without a consistent effect on the Delta Isc. Methazolamide also reduced the Jsright-arrow m by 39% but did not affect the Delta Isc. When carbonic anhydrase-dependent HCO<SUP>−</SUP><SUB>3</SUB> secretion was isolated by using a CO2-gassed, HCO<SUP>−</SUP><SUB>3</SUB>-free Ringer bath, forskolin stimulated the Jsright-arrow m and Isc (+0.7 and +2.0, respectively) across CFTR(+) but not CFTR(-) duodenum. Under these conditions, luminal Cl- substitution or DIDS abolished the Jsright-arrow m but not the Delta Isc. It was concluded that cAMP-stimulated HCO<SUP>−</SUP><SUB>3</SUB> secretion across the duodenum involves 1) electrogenic secretion via a CFTR HCO<SUP>−</SUP><SUB>3</SUB> conductance and 2) electroneutral secretion via a CFTR-dependent Cl-/ HCO<SUP>−</SUP><SUB>3</SUB> exchange process that is closely associated with the carbonic anhydrase activity of the epithelium.

cystic fibrosis; cystic fibrosis transmembrane conductance regulator; chloride secretion; chloride/bicarbonate exchanger; anion exchanger; pH stat


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