The antifungal antibiotic, clotrimazole, inhibits Cl- secretion by polarized monolayers of human colonic epithelial cells.
The antifungal antibiotic, clotrimazole, inhibits Cl- secretion by polarized monolayers of human colonic epithelial cells.
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DOI：
10.1172/jci119012
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发表时间：
1996-11
期刊：
影响因子：
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通讯作者：
P. Rufo;Lianwei Jiang;S. Moe;C. Brugnara;Seth L. Alper;W. I. Lencer
中科院分区：
文献类型：
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作者：
P. Rufo;Lianwei Jiang;S. Moe;C. Brugnara;Seth L. Alper;W. I. Lencer
氯霉唑（CLT）通过体外抑制Ca++依赖性（Gardos） K+通道来防止人HbSS红细胞脱水（1993）。[j] .中华临床医学杂志，1996,(2):1 - 2。[j] .临床医学杂志。97:1227-1234。肠隐窝上皮细胞的基底外侧膜K+通道也参与促分泌剂刺激的Cl-分泌。我们检测了CLT通过抑制K+转运来阻断肠道Cl-分泌的能力。通过T84细胞单层的短路电流（Isc）测量Cl-的分泌。CLT可逆地抑制对cAMP-和Ca2+依赖性激动剂的Cl-分泌反应，IC50值约为5微米。当CLT应用于基底外侧细胞表面时，抑制作用的发生速度更快。通过同位素通量测量评估，CLT处理对顶端Cl通道和基底侧NaK2Cl共转运体活性没有影响。相反，CLT强烈抑制基底外侧86Rb外排。这些数据提供了证据，证明CLT可可逆地抑制cAMP-、cGMP-或Ca2+依赖性激动剂在T84细胞中引起的Cl-分泌。CLT远端作用于cAMP和Ca2+信号的产生，并似乎直接抑制基底外侧K+通道。CLT及相关药物可作为人类和动物的新型止泻剂。
Clotrimazole (CLT) prevents dehydration of the human HbSS red cell through inhibition of Ca++-dependent (Gardos) K+ channels in vitro (1993. J. Clin Invest. 92:520-526.) and in patients (1996. J. Clin Invest. 97:1227-1234.). Basolateral membrane K+ channels of intestinal crypt epithelial cells also participate in secretagogue-stimulated Cl- secretion. We examined the ability of CLT to block intestinal Cl- secretion by inhibition of K+ transport. Cl- secretion was measured as short-circuit current (Isc) across monolayers of T84 cells. CLT reversibly inhibited Cl- secretory responses to both cAMP- and Ca2+-dependent agonists with IC50 values of approximately 5 microM. Onset of inhibition was more rapid when CLT was applied to the basolateral cell surface. Apical Cl- channel and basolateral NaK2Cl cotransporter activities were unaffected by CLT treatment as assessed by isotopic flux measurement. In contrast, CLT strongly inhibited basolateral 86Rb efflux. These data provide evidence that CLT reversibly inhibits Cl- secretion elicited by cAMP-, cGMP-, or Ca2+-dependent agonists in T84 cells. CLT acts distal to the generation of cAMP and Ca2+ signals, and appears to inhibit basolateral K+ channels directly. CLT and related drugs may serve as novel antidiarrheal agents in humans and animals.