title: Mechanism of the vasodilator effect of mono-oxygenated xanthones: a structure-activity relationship study.
abstract: The present study characterized the mechanisms involved in the vasodilator effect of two mono-oxygenated xanthones, 4-hydroxyxanthone and 4-methoxyxanthone. 9-Xanthenone, the base structure of xanthones, was used for comparison. 4-Hydroxyxanthone and 9-xanthenone induced a concentration-dependent and endothelium-independent vasodilator effect in arteries precontracted with phenylephrine (0.1 µmol · L-1) or KCl (50 mmol · L-1). 4-Methoxyxanthone induced a concentration-dependent vasodilator effect in arteries precontracted with phenylephrine, which was partially endothelium-dependent, and involved production of nitric oxide. In endothelium-denuded arteries precontracted with KCl, the vasodilator effect of 4-methoxyxanthone was abolished. The vasodilator effect of 4-hydroxyxanthone (96.22 ± 2.10 %) and 4-methoxyxanthone (96.57 ± 12.40 %) was significantly higher than observed with 9-xanthenone (53.63 ± 8.31 %). The presence of an oxygenated radical in position 4 made 4-hydroxyxanthone (pIC50 = 4.45 ± 0.07) and 4-methoxyxanthone (pIC50 = 5.04 ± 0.09) more potent as a vasodilator than 9-xanthenone (pIC50 = 3.92 ± 0.16). In addition, 4-methoxyxanthone was more potent than the other two xanthones. Ca2+ transients in vascular smooth muscle cells elicited by high K+ were abolished by 4-hydroxyxanthone and 9-xanthenone. The endothelium-independent effect of 4-methoxyxanthone was abolished by inhibition of K+ channels by tetraethylammonium. The current work shows that an oxygenated group in position 4 is essential to achieve Emax and to increase the potency of xanthones as vasodilators. Substitution of an OH by OCH3 in position 4 increases the potency of the vasodilator effect and changes the underling mechanism of action from the blockade of L-type calcium channels to an increase in NO production and activation of K+ channels.
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Thiago F
authors.initials: TF
authors.lastname: Diniz
authors.forename: Aline C
authors.initials: AC
authors.lastname: Pereira
authors.forename: Luciano S A
authors.initials: LS
authors.lastname: Capettini
authors.forename: Marcelo H
authors.initials: MH
authors.lastname: Santos
authors.forename: Tanus J
authors.initials: TJ
authors.lastname: Nagem
authors.forename: Virginia S
authors.initials: VS
authors.lastname: Lemos
authors.forename: Steyner F
authors.initials: SF
authors.lastname: Cortes
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology*; D044004:Xanthones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000591001:4-hydroxyxanthone; C000591002:4-methoxyxanthone; D014665:Vasodilator Agents; D044004:Xanthones; D009569:Nitric Oxide; D002118:Calcium