EFFECTS OF SULFONYLUREAS ON CAMP-STIMULATED CL- TRANSPORT VIA THE CYSTIC-FIBROSIS GENE-PRODUCT IN HUMAN EPITHELIAL-CELLS

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 Cl-36(-) in the epithelial cell line T84 which stably expresses CFTR. Neither glibenclamide (30 mu M), tolbutamide (1 mM) nor diazoxide (100 mu M) significantly affected forskolin-activated Cl-36(-) 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.