Dietary polyphenols have been associated with many beneficial cardiovascular effects. However, these effects are rather attributed to small phenolic metabolites formed by the gut microbiota, which reach sufficient concentrations in systemic circulation. 4-Methylcatechol (4-MC) is one such metabolite. As it is shown to possess considerable vasorelaxant effects, this study aimed to unravel its mechanism of action. To this end, experimental in vitro and in silico approaches were employed. In the first step, isometric tension recordings were performed on rat aortic rings. 4-MC potentiated the effect of cyclic nucleotides, but the effect was not mediated by either soluble guanylyl cyclase (sGC), modification of cyclic adenosine monophosphate levels, or protein kinase G. Hence, downstream targets such as calcium or potassium channels were considered. Inhibition of voltage-gated K⁺ channels (K_V) markedly decreased the effect of 4-MC, and vasodilation was partly decreased by inhibition of the K_V7 isoform. Contrarily, other types of K⁺ channels or L-type Ca²⁺ channels were not involved. In silico reverse docking confirmed that 4-MC binds to K_V7.4 through hydrogen bonding and hydrophobic interactions. In particular, it interacts with two crucial residues for K_V7.4 activation: Trp242 and Phe246. In summary, our findings suggested that 4-MC exerts vasorelaxation by opening K_V channels with the involvement of K_V7.4.

中文翻译：

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槲皮素代谢物 4-甲基儿茶酚通过电压门控钾 （KV） 通道引起血管舒张


膳食多酚与许多有益的心血管影响有关。然而，这些影响更归因于肠道微生物群形成的小酚类代谢物，这些代谢物在体循环中达到足够的浓度。4-甲基邻苯二酚 （4-MC） 就是这样一种代谢物。由于它被证明具有相当大的血管舒张作用，本研究旨在揭示其作用机制。为此，采用了实验性体外和计算机方法。第一步，对大鼠主动脉环进行等长张力记录。4-MC 增强了环核苷酸的作用，但这种作用不是由可溶性鸟苷酸环化酶 （sGC）、环腺苷单磷酸水平的修饰或蛋白激酶 G 介导的。因此，考虑了钙或钾通道等下游靶标。抑制电压门控 K⁺ 通道 （K_V） 显着降低 4-MC 的作用，抑制 K_V7 亚型部分降低血管舒张。相反，不涉及其他类型的 K⁺ 通道或 L 型 Ca²⁺ 通道。计算机反向对接证实 4-MC 通过氢键和疏水相互作用与 K_V7.4 结合。特别是，它与 K_V7.4 激活的两个关键残基相互作用：Trp242 和 Phe246。总之，我们的研究结果表明，4-MC 在 K_V7.4 的参与下通过打开 KV 通道来发挥血管舒张作用。