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Cellular mechanisms underlying the inhibitory effect of flufenamic acid on chloride secretion in human intestinal epithelial cells.

Abstract：

:Intestinal Cl- 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 Cl- secretion in human intestinal epithelial (T84) cells. FFA inhibited cAMP-dependent Cl- secretion in T84 cell monolayers with IC50 of ∼8 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 Cl- 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 Cl- secretion with IC50 of ∼10 μM. FFA inhibited activities of Ca2+-activated Cl- channels and KCa3.1, a Ca2+-activated basolateral K+ channels, but had no effect on activities of Na+-K+-Cl- cotransporters and Na+-K+ ATPases. These results indicate that FFA inhibits both cAMP and Ca2+-dependent Cl- secretion by suppressing activities of both apical Cl- channels and basolateral K+ channels. FFA and other fenamate drugs may be useful in the treatment of secretory diarrheas.

journal_name

J Pharmacol Sci

journal_title

Journal of pharmacological sciences

authors

Pongkorpsakol P,Yimnual C,Chatsudthipong V,Rukachaisirikul V,Muanprasat C

doi

10.1016/j.jphs.2017.05.009

subject

Has Abstract

pub_date

2017-06-01 00:00:00

pages

93-100

issue

2

eissn

1347-8613

issn

1347-8648

pii

S1347-8613(17)30085-3

journal_volume

134

pub_type

杂志文章

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