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

Autor: Dias P; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Kralove, Czech Republic; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA; Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA. Electronic address: patriciaalvdias@gmail.com., Salam R; Department of Biophysics and Physical Chemistry, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Kralove, Czech Republic. Electronic address: salamr@faf.cuni.cz., Moravcová M; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Kralove, Czech Republic. Electronic address: moravcovamo@faf.cuni.cz., Saadat S; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Kralove, Czech Republic. Electronic address: saadatbs@faf.cuni.cz., Pourová J; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Kralove, Czech Republic. Electronic address: pourova@faf.cuni.cz., Vopršalová M; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Kralove, Czech Republic. Electronic address: voprsalova@faf.cuni.cz., Jirkovský E; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Kralove, Czech Republic. Electronic address: jirkovskye@faf.cuni.cz., Tebbens JD; Department of Biophysics and Physical Chemistry, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Kralove, Czech Republic. Electronic address: jurjend@faf.cuni.cz., Mladěnka P; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Kralove, Czech Republic. Electronic address: mladenkap@faf.cuni.cz.
Jazyk: angličtina
Zdroj: Vascular pharmacology [Vascul Pharmacol] 2024 Sep; Vol. 156, pp. 107418. Date of Electronic Publication: 2024 Aug 17.
DOI: 10.1016/j.vph.2024.107418
Abstrakt: 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 50 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 2+ -channels. By using two inhibitors, activation of voltage-gated potassium channels (K V ) was found to be involved in the mechanism of action. This was corroborated by docking analysis of 3-MOC with the K V 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier Inc.)
Databáze: MEDLINE
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