Ducts isolated from the pancreas of CFTR-null mice secrete fluid.
The pancreatic pathology in cystic fibrosis (CF) is normally attributed to the failure of ductal fluid secretion resulting from the lack of functional CF transmembrane conductance regulator (CFTR). However, murine models of CF show little or no pancreatic pathology. To resolve this dichotomy we analysed the transport mechanisms involved in fluid and electrolyte secretion by pancreatic ducts isolated from CFTR-null mice. Experiments were performed on cultured interlobular duct segments isolated from the pancreas of the Cftr(tm1Cam) strain of CFTR-null mouse. Fluid secretion to the closed luminal space was measured by video microscopy. The secretory response of ducts isolated from CF mice to cAMP-elevating agonists forskolin and secretin was significantly reduced compared with wild type but not abolished. The Cl(-)- and HCO(3) (-) -dependent components of the ductal secretion were affected equally by the absence of CFTR. The secretory response to carbachol stimulation was unaltered in CF ducts. Loading the ductal cells with the Ca2+ chelator BAPTA completely abolished carbachol-evoked secretion, but did not affect forskolin-evoked secretion in CF or wild-type ducts. We conclude that pancreatic duct cells from CF mice can secrete a significant amount of water and electrolytes by a cAMP-stimulated mechanism that is independent of CFTR and cannot be ascribed to the activation of calcium-activated chloride channels.
Pascua
Patricia
P
Departamento de Fisiología y Farmacología, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
García
Mónica
M
Fernández-Salazar
M Paz
MP
Hernández-Lorenzo
M Pilar
MP
Calvo
José J
JJ
Colledge
William H
WH
Case
R Maynard
RM
Steward
Martin C
MC
San Román
José I
JI
D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018181:Mice, Inbred CFTR; D010183:Pancreatic Ducts / Q000378:metabolism*; D012633:Secretin / Q000494:pharmacology
D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012633:Secretin; D005576:Colforsin