Prevention of toxin-induced intestinal ion and fluid secretion by a small-molecule CFTR inhibitor
Prevention of toxin-induced intestinal ion and fluid secretion by a small-molecule CFTR inhibitor
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DOI：
10.1053/j.gastro.2003.11.005
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发表时间：
2004-02-01
期刊：
影响因子：
29.4
通讯作者：
Verkman, AS
中科院分区：
文献类型：
--
作者：
Thiagarajah, JR;Broadbent, T;Verkman, AS
Background & Aims: The cystic fibrosis transmembrane conductance regulator (CFTR) provides an important apical route for Cl- secretion across intestinal epithelia. A thiazolidinone-type CFTR blocker (CFTRinh-172) reduced cholera toxin-induced fluid accumulation in mouse intestinal loops. Here, we characterize the efficacy and pharmacodynamics of CFTRinh-172 in blocking cAMP and cGMP induced Cl-/fluid secretion in rodent and human intestine. Methods & Results: CFTRinh-172 inhibited cAMP and cGMP agonist induced short-circuit current by >95% in T84 colonic epithelial cells (K-I similar to 3 mumol/L) and in mouse and human intestinal sheets (K-I similar to 9 mmuol/L). A single intraperitoneal injection of CFTRinh-172 (200 mug) blocked intestinal fluid secretion in a rat closed-loop model by >90% for cholera toxin and >70% for STa Escherichia coli toxin. In mice, CFTRinh-172 (20 mug) inhibited cholera toxin-induced intestinal fluid secretion by 90% (persistence t(1/2) similar to10 hours, K-I similar to 5 mug) and STa toxin by 75% (K-I similar to 10 mug). Tissue distribution and pharmacokinetic studies indicated intestinal CFTRinh-172 accumulation facilitated by enterohepatic circulation. An oral CFTRinh-172 preparation reduced fluid secretion by >90% in a mouse open-loop cholera model. Conclusions: A small molecule CFTR blocker markedly reduced intestinal ion and fluid secretion caused by cAMP/cGMP-dependent bacterial enterotoxins. CFTR inhibition may thus reduce fluid secretion in infectious secretory diarrheas.
