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Vasorelaxant effects of 3-methoxycatechol are not via direct activation of voltage-gated potassium channels

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Jan 20, 2025 version files 505.39 KB
Feb 10, 2025 version files 507.10 KB
Feb 12, 2025 version files 444.27 KB

Abstract

The Kv7 (KCNQ) family of voltage-gated potassium (Kv) channels comprises Kv7.1-7.5, which are expressed throughout the human body where they regulate numerous essential physiological processes . As such, there has been a lot of interest in developing and identifying small molecules that can modulate specific Kv7 channel isoforms. We previously discovered that plant metabolites such as aloperine from Sophora flavescens (Ku Shen), carnosol and carnosic acid from rosemary (Salvia rosmarinus), and gallic acid and tannic acid from Native American bark extracts are efficacious Kv7.5 channel activators with prominent vasorelaxant effects. Kv7.1, Kv7.4, and Kv7.5 channels are important regulators of smooth muscle contractility, regulating the membrane potential of vascular smooth muscle and subsequently vascular tone. Pharmacological targeting of these Kv7 channels with pan-Kv7 inhibitors XE-991 and linopirdine provokes membrane depolarization and vasoconstriction, while several structurally disparate activators enhance Kv7 channel currents resulting in membrane hyperpolarization and vasorelaxation. Recently, it was concluded based in ex vivo pharmacology and in silico docking that the vasorelaxant effects of 3-methoxycatechol (3-MOC) arise from direct binding to and activation of Kv channels in the vascular smooth muscle, specifically Kv7.4, but the direct effects on Kv channels were not substantiated experimentally. Here, we report that the mechanism of vasodilation by 3-MOC is not via direct Kv channel activation and strongly advise against pharmacological target assumptions using non-experimentally validated in silico docking, a technique not appropriate for this purpose.