Functional Control Systems, Graduate School of Engineering and Science, Shibaura Institute of Technology, Japan.
Systems Engineering and Science, Graduate School of Engineering and Science, Shibaura Institute of Technology, Japan.
Biochem Pharmacol. 2023 Aug;214:115682. doi: 10.1016/j.bcp.2023.115682. Epub 2023 Jul 8.
Intervention trials confirmed that blood flow-mediated dilatation increases significantly after intake of astringent (-)-epicatechin (EC) oligomers (procyanidins)-rich foods, but the mechanism remains unclear. We have previously found that procyanidins can activate the sympathetic nervous and subsequently increase blood flow. Here, we examined whether procyanidin-derived reactive oxygen species (ROS) activate transient receptor potential (TRP) channels in gastrointestinal sensory nerves and consequently induce sympathoexcitation. We evaluated the redox properties of EC and its tetramer cinntamtannin A2 (A2) at pH 5 or 7, mimicking plant vacuole or oral cavity/small intestine using a luminescent probe. At pH 5, A2 or EC showed O scavenging ability, but they promoted O generation at pH 7. We observed blood flow in rat cremaster arterioles using laser Doppler, a single oral dose of 10 µg/kg A2 markedly increased blood flow, while EC showed little activity. This change with A2 was significantly dampened by co-administration of adrenaline blocker, ROS scavenger N-acetyl-L-cysteine (NAC), TRP vanilloid 1, or ankyrin 1 antagonist. We also performed a docking simulation of EC or A2 with the binding site of a typical ligand for each TRP channel and calculated the respective binding affinities. The binding energies were notably higher for A2 than typical ligands, suggesting that A2 is less likely to bind to these sites. ROS produced at neutral pH following the orally administered A2 to the gastrointestinal tract could activate TRP channels, triggering sympathetic hyperactivation and causing hemodynamic changes.
干预试验证实，摄入富含收敛性（-）-表儿茶素（EC）低聚物（原花青素）的食物后，血流介导的扩张明显增加，但机制尚不清楚。我们之前发现原花青素可以激活交感神经系统，随后增加血流量。在这里，我们研究了原花青素衍生的活性氧（ROS）是否会激活胃肠道感觉神经中的瞬时受体电位（TRP）通道，从而诱导交感兴奋。我们评估了 EC 及其四聚体 cinntamtannin A2（A2）在 pH5 或 7 时的氧化还原特性，使用发光探针模拟植物液泡或口腔/小肠。在 pH5 时，A2 或 EC 具有 O 清除能力，但在 pH7 时它们会促进 O 的生成。我们使用激光多普勒观察大鼠提睾肌动静脉中的血流，单次口服 10μg/kg 的 A2 可显著增加血流，而 EC 几乎没有活性。这种变化在与肾上腺素阻滞剂、ROS 清除剂 N-乙酰-L-半胱氨酸（NAC）、TRP 香草素 1 或锚蛋白 1 拮抗剂共同给药时明显减弱。我们还对 EC 或 A2 与每个 TRP 通道的典型配体的结合位点进行了对接模拟，并计算了各自的结合亲和力。与典型配体相比，A2 的结合能明显更高，这表明 A2 不太可能与这些位点结合。胃肠道中口服 A2 后在中性 pH 下产生的 ROS 可激活 TRP 通道，引发交感神经过度兴奋并引起血液动力学变化。
