Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8533160 | Journal of Pharmacological Sciences | 2017 | 8 Pages |
Abstract
Intestinal Clâ secretion is involved in the pathogenesis of secretory diarrheas including cholera. We recently demonstrated that flufenamic acid (FFA) suppressed Vibrio cholerae El Tor variant-induced intestinal fluid secretion via mechanisms involving AMPK activation and NF-κB-suppression. The present study aimed to investigate the effect of FFA on transepithelial Clâ secretion in human intestinal epithelial (T84) cells. FFA inhibited cAMP-dependent Clâ secretion in T84 cell monolayers with IC50 of â¼8 μM. Other fenamate drugs including tolfenamic acid, meclofenamic acid and mefenamic acid exhibited the same effect albeit with lower potency. FFA also inhibited activities of CFTR, a cAMP-activated apical Clâ channel, and KCNQ1/KCNE3, a cAMP-activated basolateral K+ channel. Mechanisms of CFTR inhibition by FFA did not involve activation of its negative regulators. Interestingly, FFA inhibited Ca2+-dependent Clâ secretion with IC50 of â¼10 μM. FFA inhibited activities of Ca2+-activated Clâ channels and KCa3.1, a Ca2+-activated basolateral K+ channels, but had no effect on activities of Na+-K+-Clâ cotransporters and Na+-K+ ATPases. These results indicate that FFA inhibits both cAMP and Ca2+-dependent Clâ secretion by suppressing activities of both apical Clâ channels and basolateral K+ channels. FFA and other fenamate drugs may be useful in the treatment of secretory diarrheas.
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Authors
Pawin Pongkorpsakol, Chantapol Yimnual, Varanuj Chatsudthipong, Vatcharin Rukachaisirikul, Chatchai Muanprasat,