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 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-dependent Cl secretion with IC of ∼10 μM. FFA inhibited activities of Ca-activated Cl channels and K3.1, a Ca-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-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.