The quercetin metabolite 4-methylcatechol causes vasodilation via voltage-gated potassium (K_V) channels

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.