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

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 IC ₅₀ 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 Ca ²⁺ -dependent Cl ^- secretion with IC ₅₀ of ∼10 μM. FFA inhibited activities of Ca ²⁺ -activated Cl ^- channels and K _Ca 3.1, a Ca ²⁺ -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 Ca ²⁺ -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.
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