CFTR mediates cAMP- and Ca2+-activated duodenal epithelial HCO3- secretion.
The role of the cystic fibrosis transmembrane conductance regulator (CFTR) in duodenal alkaline secretion has not been directly examined. The aims of this series of experiments were to determine if CFTR mediates basal and stimulated duodenal epithelial HCO3- secretion. Utilizing the cystic fibrosis murine model (cftr(m1UNC)), we compared normal [CFTR(+/+)] littermates (34-46 days old) with CFTR(-/-) animals (34-39 days old). Anesthesia was induced and maintained with intraperitoneal Hypnorm-midazolam. The proximal duodenum (4-7 mm) was cannulated and perfused with 154 mM NaCl. Either forskolin (10(-6)-10(-4) M) or carbachol (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 back 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 micromol x cm(-1) x h(-1)). Moreover, in CFTR(-/-) mice, both forskolin- 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 micromol x cm(-1) x h(-1), respectively; P < 0.01). In conclusion, CFTR plays a significant role in mediating basal, cAMP-, and Ca2+-activated duodenal epithelial HCO3- secretion.
Hogan
D L
DL
Biomedical Laboratory, Odense University, Denmark.
Crombie
D L
DL
Isenberg
J I
JI
Svendsen
P
P
Schaffalitzky de Muckadell
O B
OB
Ainsworth
M A
MA
D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D002118:Calcium / Q000502:physiology*; D002217:Carbachol / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D004386:Duodenum / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains
D001639:Bicarbonates; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D002217:Carbachol; D000242:Cyclic AMP; D002118:Calcium