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Abstract：
Although capsaicin has been studied extensively as an activator of the transient receptor potential vanilloid cation channel subtype 1 (TRPV1) channels in sensory neurons, little is known about its TRPV1-independent actions in gastrointestinal health and disease. Here, we aimed to investigate the pharmacological actions of capsaicin as a food additive and medication on intestinal ion transporters in mouse models of ulcerative colitis (UC). The short-circuit current (Isc) of the intestine from WT, TRPV1-, and TRPV4-KO mice were measured in Ussing chambers, and Ca2+ imaging was performed on small intestinal epithelial cells. We also performed Western blots, immunohistochemistry, and immunofluorescence on intestinal epithelial cells and on intestinal tissues following UC induction with dextran sodium sulfate. We found that capsaicin did not affect basal intestinal Isc but significantly inhibited carbachol- and caffeine-induced intestinal Isc in WT mice. Capsaicin similarly inhibited the intestinal Isc in TRPV1 KO mice, but this inhibition was absent in TRPV4 KO mice. We also determined that Ca2+ influx via TRPV4 was required for cholinergic signaling-mediated intestinal anion secretion, which was inhibited by capsaicin. Moreover, the glucose-induced jejunal Iscvia Na+/glucose cotransporter was suppressed by TRPV4 activation, which could be relieved by capsaicin. Capsaicin also stimulated ouabain- and amiloride-sensitive colonic Isc. Finally, we found that dietary capsaicin ameliorated the UC phenotype, suppressed hyperaction of TRPV4 channels, and rescued the reduced ouabain- and amiloride-sensitive Isc. We therefore conclude that capsaicin inhibits intestinal Cl- secretion and promotes Na+ absorption predominantly by blocking TRPV4 channels to exert its beneficial anti-colitic action.
摘要：
尽管辣椒素已被广泛研究为感觉神经元中瞬时受体电位香草酸阳离子通道亚型1（TRPV1）通道的激活剂，对其在胃肠道健康和疾病中不依赖TRPV1的作用知之甚少。这里,我们旨在研究辣椒素作为食品添加剂和药物对溃疡性结肠炎（UC）小鼠模型肠离子转运蛋白的药理作用。来自WT的肠的短路电流(Isc)，TRPV1-,和TRPV4-KO小鼠在Ussing室内测量，对小肠上皮细胞进行Ca2+成像。我们还进行了西方印迹，免疫组织化学，右旋糖酐硫酸钠诱导UC后肠上皮细胞和肠组织的免疫荧光。我们发现辣椒素不会影响WT小鼠的基础肠道Isc，但会显着抑制卡巴胆碱和咖啡因诱导的肠道Isc。辣椒素同样抑制TRPV1KO小鼠的肠道Isc,但这种抑制作用在TRPV4KO小鼠中不存在。我们还确定通过TRPV4的Ca2+内流是胆碱能信号介导的肠阴离子分泌所必需的，被辣椒素抑制。此外，葡萄糖诱导的空肠IscviaNa+/葡萄糖协同转运蛋白被TRPV4激活抑制，辣椒素可以缓解。辣椒素还刺激了对哇巴因和阿米洛利敏感的结肠Isc。最后,我们发现，饮食辣椒素改善UC表型，抑制TRPV4通道的过度反应，并拯救了对乌巴巴因和阿米洛利敏感的Isc。因此，我们得出结论，辣椒素主要通过阻断TRPV4通道来抑制肠道Cl-分泌并促进Na吸收，以发挥其有益的抗绞痛作用。
