3-methoxycatechol causes vasodilation likely via K V channels: ex vivo, in silico docking and in vivo study

• Published in: Vascular pharmacology 2024-09, Vol.156, p.107418
• Main Authors: Dias, Patrícia, Salam, Rudy, Moravcová, Monika, Saadat, Saina, Pourová, Jana, Vopršalová, Marie, Jirkovský, Eduard, Tebbens, Jurjen Duintjer, Mladěnka, Přemysl
• Format: Article
• Language: English
• Subjects: Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - metabolism; Arterial Pressure - drug effects; Catechols - chemistry; Catechols - pharmacology; Coronary Vessels - drug effects; Coronary Vessels - metabolism; Cyclic GMP - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hypertension - drug therapy; Hypertension - metabolism; Hypertension - physiopathology; Male; Mesenteric Arteries - drug effects; Mesenteric Arteries - metabolism; Molecular Docking Simulation; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Potassium Channels, Voltage-Gated - antagonists & inhibitors; Potassium Channels, Voltage-Gated - drug effects; Potassium Channels, Voltage-Gated - metabolism; Rats; Rats, Inbred SHR; Sex Factors; Structure-Activity Relationship; Swine; Vasodilation - drug effects; Vasodilator Agents - chemistry; Vasodilator Agents - pharmacology
• ISSN: 1879-3649

Substituted catechols include both natural and synthetic compounds found in the environment and foods. Some of them are flavonoid metabolites formed by the gut microbiota which are absorbed afterwards. Our previous findings showed that one of these metabolites, 4-methylcatechol, exerts potent vasorelaxant effects in rats. In the current study, we aimed at testing of its 22 structural congeners in order to find the most potent structure and to investigate the mechanism of action. 3-methoxycatechol (3-MOC), 4-ethylcatechol, 3,5-dichlorocatechol, 4-tert-butylcatechol, 4,5-dichlorocatechol, 3-fluorocatechol, 3-isopropylcatechol, 3-methylcatechol and the parent 4-methylcatechol exhibited high vasodilatory activities on isolated rat aortic rings with EC s ranging from ∼10 to 24 μM. Some significant sex-differences were found. The most potent compound, 3-MOC, relaxed also resistant mesenteric artery but not porcine coronary artery, and decreased arterial blood pressure in both male and female spontaneously hypertensive rats in vivo without affecting heart rate. It potentiated the vasodilation mediated by cAMP and cGMP, but did not impact L-type Ca -channels. By using two inhibitors, activation of voltage-gated potassium channels (K ) was found to be involved in the mechanism of action. This was corroborated by docking analysis of 3-MOC with the K 7.4 channel. None of the most active catechols decreased the viability of the A-10 rat embryonic thoracic aorta smooth muscle cell line. Our findings showed that various catechols can relax vascular smooth muscles and hence could provide templates for developing new antihypertensive vasodilator agents without affecting coronary circulation.