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

被引:28
作者
Mun, EC
Mayol, JM
Riegler, M
O'Brien, TC
Farokhzad, OC
Song, JC
Pothoulakis, C
Hrnjez, BJ
Matthews, JB
机构
[1] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA
[2] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Gastroenterol, Boston, MA USA
关键词
D O I
10.1016/S0016-5085(98)70432-9
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background & Aims: Phenylimidazothiazoles have recently been shown to activate wild-type and mutant cystic fibrosis transmembrane conductance regulator (CFTR) CI- 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 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. Selective permeabilization of apical or basolateral membranes with the monovalent ionophore nystatin was used to isolate basolateral K+ and apical CI- channel activity, respectively. Rb-86(+) 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 Ca2+ agonist carbachol. In permeabilized T84 monolayers, phenylimidazothiazoles weakly activated apical CI- currents (consistent with their reported action on CFTR) and did not affect bumetanide-sensitive or bumetanide-insensitive Rb-86(+) uptake. Instead, they profoundly inhibited 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 and native colon, an effect that outweighs their ability to activate apical CI- channels.
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页码:1257 / 1267
页数:11
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