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Cyclic AMP-activated intestinal Cl −  secretion plays an important role in pathogenesis of cholera. This study aimed to investigate the effect of diclofenac on cAMP-activated Cl −  secretion, its underlying mechanisms, and possible application in the treatment of cholera. Diclofenac inhibited cAMP-activated Cl −  secretion in human intestinal epithelial (T84) cells with IC 50  of ∼20 µM. The effect required no cytochrome P450 enzyme-mediated metabolic activation. Interestingly, exposures of T84 cell monolayers to diclofenac, either in apical or basolateral solutions, produced similar degree of inhibitions. Analyses of the apical Cl −  current showed that diclofenac reversibly inhibited CFTR Cl −  channel activity (IC 50 ∼10 µM) via mechanisms not involving either changes in intracellular cAMP levels or CFTR channel inactivation by AMP-activated protein kinase and protein phosphatase. Of interest, diclofenac had no effect on Na + -K +  ATPases and Na + -K + -Cl −  cotransporters, but inhibited cAMP-activated basolateral K +  channels with IC 50  of ∼3 µM. In addition, diclofenac suppressed Ca 2+ -activated Cl −  channels, inwardly rectifying Cl −  channels, and Ca 2+ -activated basolateral K +  channels. Furthermore, diclofenac (up to 200 µM; 24 h of treatment) had no effect on cell viability and barrier function in T84 cells. Importantly, cholera toxin (CT)-induced Cl −  secretion across T84 cell monolayers was effectively suppressed by diclofenac. Intraperitoneal administration of diclofenac (30 mg/kg) reduced both CT and  Vibrio cholerae -induced intestinal fluid secretion by ∼70% without affecting intestinal fluid absorption in mice. Collectively, our results indicate that diclofenac inhibits both cAMP-activated and Ca 2+ -activated Cl −  secretion by inhibiting both apical Cl −  channels and basolateral K +  channels in intestinal epithelial cells. Diclofenac may be useful in the treatment of cholera and other types of secretory diarrheas resulting from intestinal hypersecretion of Cl − .

Inhibition of cAMP-Activated Intestinal Chloride Secretion by Diclofenac: Cellular Mechanism and Potential Application in Cholera