Levamisole inhibits intestinal Cl − secretion via basolateral K + channel blockade

Background & Aims: Phenylimidazothiazoles have recently been shown to activate wild-type and mutant cystic fibrosis transmembrane conductance regulator (CFTR) Cl − channels in transfected cells and were proposed as therapy for cystic fibrosis. The aim of this study was to investigate the effects of phenylimidazothiazoles on regulated transepithelial Cl − transport in intact epithelia. Methods: T84 intestinal epithelial cells grown on permeable supports and stripped human colonic mucosal sheets were studied by conventional current-voltage clamping. Selective permeabilization of apical or basolateral membranes with the monovalent ionophore nystatin was used to isolate basolateral K + and apical Cl − channel activity, respectively. 86Rb + uptake was assessed for Na/K/2Cl cotransporter and Na +,K +–adenosine triphosphatase activity. Results: In T84 monolayers and human colon, levamisole and its brominated derivative bromotetramisole failed to activate transepithelial secretion. In fact, these compounds dose-dependently inhibited secretory responses to the cyclic adenosine monophosphate agonist forskolin and the Ca 2+ agonist carbachol. In permeabilized T84 monolayers, phenylimidazothiazoles weakly activated apical Cl − currents (consistent with their reported action on CFTR) and did not affect bumetanide-sensitive or bumetanide-insensitive 86Rb + uptake. Instead, they profoundly inhibited the basolateral Ba 2+-sensitive and Ba 2+-insensitive K + currents. Conclusions: Phenylimidazothiazoles block K + channels required for Cl −-secretory responses elicited by diverse pathways in model epithelia and native colon, an effect that outweighs their ability to activate apical Cl − channels. GASTROENTEROLOGY 1998;114:1257-1267