trans-δ-Viniferin inhibits Ca²⁺-activated Cl^- channels and improves diarrhea symptoms

Ca²⁺-activated Cl^- channels (CaCCs) wildly exist in many tissues which play an important role in ion transport and excitation conduction, especially fluid secretion and smooth muscle contraction in epithelial tissues. TMEM16A as a classic CaCC expresses in the intestine, and has become a potential target of intestinal physiological and pathological researches and therapeutic drug screening. In this study, we identified trans-δ-viniferin (TVN), a resveratrol dimmer, could inhibit TMEM16A activity in TMEM16A expressed FRT cells with IC₅₀ of 19.7 μM, it also prevented Ca²⁺-activated Cl^- current in HT-29 cells with IC₅₀ of 4.65 μM and in colonic mucosa. In the mechanism studies, TVN showed no significant inhibition on CFTR and basal Na⁺/K⁺-ATPase in both intestinal epithelial cells and colonic tissues, except for inhibition of calcium concentration and Ca²⁺-activated K⁺ channel to some degree. In anti-diarrheal studies, TVN could effectively prevent diarrhea caused by rotavirus infection and reduce the pellet number in IBS-D mice. These physiological effects are at least partially attributed to the inhibitory effect of TVN on CaCC-mediated intestinal fluid secretion and the reduction of smooth muscle contraction force by inhibiting TMEM16A. Collectively, the present study identified a new pharmacological target of TVN which provided the theoretical basis for the application of TVN in the treatment of rotavirus-infected diarrhea and IBS-D.