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 conductanc e regulator (CFTR) CI- channels in transfected cells and were proposed as therapy for cystic fibrosis. The aim of this study was to investig ate the effects of phenylimidazothiazoles on regulated transepithelial CI- 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. Selectiv e permeabilization of apical or basolateral membranes with the monoval ent ionophore nystatin was used to isolate basolateral K+ and apical C I- channel activity, respectively. Rb-86(+) uptake was assessed for Na /K/2Cl cotransporter and Na+, K+-adenosine triphosphatase activity. Re sults: In T84 monolayers and human colon, levamisole and its brominate d derivative bromotetramisole failed to activate transepithelial secre tion. In fact, these compounds dose-dependently inhibited secretory re sponses to the cyclic adenosine monophosphate agonist forskolin and th e Ca2+ agonist carbachol. In permeabilized T84 monolayers, phenylimida zothiazoles weakly activated apical CI- currents (consistent with thei r reported action on CFTR) and did not affect bumetanide-sensitive or bumetanide-insensitive Rb-86(+) uptake. Instead, they profoundly inhib ited the basolatoral Ba2+-sensitive and Ba2+-insensitive K+ currents. Conclusions: Phenylimidazothiazoles block K+ channels required for CI- -secretory responses elicited by diverse pathways in model epithelia a nd native colon, an effect that outweighs their ability to activate ap ical CI- channels.