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 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. © 2017 the authors