title: Effects of sulphonylureas on cAMP-stimulated Cl- transport via the cystic fibrosis gene product in human epithelial cells.
abstract: The cystic fibrosis gene product (CFTR) is a Cl- channel that possesses specific binding sites for cytosolic adenosine triphosphate (ATP) and is activated by cyclic adenosine monophosphate (cAMP)-dependent protein kinases. We explored the possibility that CFTR shares a common pharmacology with another ATP-regulated channel protein, the ATP-sensitive K+ channel that is blocked by sulphonylureas and activated by diazoxide. cAMP-stimulated Cl- effluxes were measured with 36Cl- in the epithelial cell line T84 which stably expresses CFTR. Neither glibenclamide (30 microM), tolbutamide (1 mM) nor diazoxide (100 microM) significantly affected forskolin-activated 36Cl- effluxes in T84 cells. In patch-clamp experiments, glibenclamide exerted only weak inhibitory effects on the whole-cell currents through CFTR with an IC50 of around 0.1 mM. Tolbutamide at 1 mM, but not at 0.1 mM, blocked a current of small amplitude which reversed near the equilibrium potential for K+ ions. We conclude that sulphonylureas and diazoxide are not effective antagonists of endogenous CFTR Cl- channels.
authors.affiliation: URA CNRS 1121, Université Paris XI, Orsay, France.
authors.forename: A S
authors.initials: AS
authors.lastname: Hongre
authors.forename: I
authors.initials: I
authors.lastname: Baró
authors.forename: B
authors.initials: B
authors.lastname: Berthon
authors.forename: D
authors.initials: D
authors.lastname: Escande
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D001798:Blood Proteins / Q000494:pharmacology*; D002460:Cell Line; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D003981:Diazoxide / Q000494:pharmacology; D004594:Electrophysiology; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D014044:Tolbutamide / Q000494:pharmacology
chemical_list: D001798:Blood Proteins; C505032:CFTR protein, human; D018118:Chloride Channels; D013453:Sulfonylurea Compounds; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D000255:Adenosine Triphosphate; D014044:Tolbutamide; D000242:Cyclic AMP; D003981:Diazoxide; D005905:Glyburide