Pawin PongkorpsakolPreedajit WongkrasantSaowanee KumpunVaranuj ChatsudthipongChatchai MuanprasatMahidol UniversitySuan Sunandha Rajabhat UniversityBangkokThailand Ministry of Education2018-11-232018-11-232015-10-05Pharmacological Research. Vol.100, (2015), 271-28010961186104366182-s2.0-84940887939https://repository.li.mahidol.ac.th/handle/20.500.14594/36293© 2015 Elsevier Ltd. All rights reserved. Piperine is the principal alkaloid in black peppers (Piper nigrum L.), which is a commonly included spice in anti-diarrheal formulations. Piperine has antispasmodic activities, but its anti-secretory effect is not known. Therefore, this study investigated the anti-secretory effect of piperine and its underlying mechanism. Piperine inhibited cAMP-mediated Cl^- secretion in human intestinal epithelial (T84) cells, similar to black pepper extract. Intraluminal administration of piperine (2 μg/loop) suppressed cholera toxin-induced intestinal fluid accumulation by ∼85% in mice. The anti-secretory mechanism of piperine was investigated by evaluating its effects on the activity of transport proteins involved in cAMP-mediated Cl^- secretion. Notably, piperine inhibited CFTR Cl^- channel activity (IC<inf>50</inf>#8'6#10 μM) without affecting intracellular cAMP levels. The mechanisms of piperine-induced CFTR inhibition did not involve MRP4-mediated cAMP efflux, AMPK or TRPV1. Piperine also inhibited cAMP-activated basolateral K⁺ channels, but it had no effect on Na⁺-K⁺-Cl^- cotransporters or Na⁺-K⁺ ATPases. Piperine suppressed Ca²⁺-activated Cl^- channels (CaCC) without affecting intracellular Ca²⁺ concentrations or Ca²⁺-activated basolateral K⁺ channels. Collectively, this study indicates that the anti-secretory effect of piperine involves the inhibition of CFTR, CaCC and cAMP-activated basolateral K⁺ channels. Piperine represents a novel class of drug candidates for the treatment of diarrheal diseases caused by the intestinal hypersecretion of Cl^-.Mahidol UniversityMedicineArticleSCOPUS10.1016/j.phrs.2015.08.012