Cellular mechanisms underlying the inhibitory effect of flufenamic acid on chloride secretion in human intestinal epithelial cells.
- Citation data:
Journal of pharmacological sciences, ISSN: 1347-8648, Vol: 134, Issue: 2, Page: 93-100
- Publication Year:
- Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics
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.