CFTR MEDIATES CAMP-ACTIVATED AND CA2-ACTIVATED DUODENAL EPITHELIAL HCO3- SECRETION()

The role of the cystic fibrosis transmembrane conductance regulator (C FTR) in duodenal alkaline secretion has not been directly examined. Th e aims of this series of experiments were to determine if CFTR mediate s basal and stimulated duodenal epithelial HCO3- secretion. Utilizing the cystic fibrosis murine model (cftr(m1UNC)), we compared normal [CF TR(+/+)] littermates (34-46 days old) with CFTR(-/-) animals (34-39 da ys old). Anesthesia was induced and maintained with intraperitoneal Hy pnorm-midazolam. The proximal duodenum (4-7 mm) was cannulated and per fused with 154 mM NaCl. Either forskolin (10(-6)-10(-4) M) or carbacho l (10(-6)-10(-3) M) was perfused intraluminally to activate adenosine 3',5'-cyclic monophosphate (cAMP)- and Ca2+-mediated HCO3- secretion, respectively. Effluent volumes were weighed and HCO3- quantitated by b ack titration. Basal HCO3- secretion was diminished significantly (P < 0.01) in CFTR( -/-) vs. normal CFTR(+/+) mice (2.8 +/- 0.5 vs. 5.3 +/ - 0.4 mu mol.cm(-1). h(-1)). Moreover, in CFTR(-/-) mice, both forskol in- and carbachol-stimulated peak HCO3- secretions were fourfold less compared with those in CFTR(+/+) Littermates (3.7 +/- 0.2 vs. 15.6 +/- 2.1 and 4.7 +/- 0.3 vs. 14.2 +/- 2.5 mu mol.cm(-1).h(-1), respectivel y; P < 0.01). In conclusion, CFTR plays a significant role in mediatin g basal, cAMP-, and Ca2+-activated duodenal epithelial HCO, secretion.