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3-methoxycatechol causes vasodilation likely via KV channels: ex vivo, in silico docking and in vivo study
P. Dias, R. Salam, M. Moravcová, S. Saadat, J. Pourová, M. Vopršalová, E. Jirkovský, JD. Tebbens, P. Mladěnka
Language English Country United States
Document type Journal Article
- MeSH
- Aorta, Thoracic drug effects metabolism MeSH
- Mesenteric Arteries * drug effects metabolism MeSH
- Arterial Pressure drug effects MeSH
- Potassium Channels, Voltage-Gated metabolism antagonists & inhibitors drug effects MeSH
- Cyclic GMP metabolism MeSH
- Hypertension drug therapy physiopathology metabolism MeSH
- Catechols * pharmacology chemistry MeSH
- Coronary Vessels drug effects metabolism MeSH
- Rats MeSH
- Disease Models, Animal MeSH
- Myocytes, Smooth Muscle drug effects metabolism MeSH
- Rats, Inbred SHR * MeSH
- Swine MeSH
- Sex Factors MeSH
- Molecular Docking Simulation * MeSH
- Muscle, Smooth, Vascular drug effects metabolism MeSH
- Vasodilation * drug effects MeSH
- Vasodilator Agents * pharmacology chemistry MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
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 EC50s 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 Ca2+-channels. By using two inhibitors, activation of voltage-gated potassium channels (KV) was found to be involved in the mechanism of action. This was corroborated by docking analysis of 3-MOC with the KV7.4 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.
References provided by Crossref.org
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- $a Dias, Patrícia $u 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
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- $a 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 EC50s 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 Ca2+-channels. By using two inhibitors, activation of voltage-gated potassium channels (KV) was found to be involved in the mechanism of action. This was corroborated by docking analysis of 3-MOC with the KV7.4 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.
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- $a Salam, Rudy $u 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
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- $a Moravcová, Monika $u 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
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- $a Saadat, Saina $u 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
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