title: Quercetin inhibits vascular superoxide production induced by endothelin-1: Role of NADPH oxidase, uncoupled eNOS and PKC.
abstract: Chronic administration of the most abundant dietary flavonoid quercetin exerts antihypertensive effects and improves endothelial function. We have investigated the effects of quercetin and its methylated metabolite isorhamnetin (1-10microM) on endothelial dysfunction and superoxide (O(2*)(-)) production induced by endothelin-1 (ET-1, 10nM). ET-1 increased the contractile response induced by phenylephrine and reduced the relaxant responses to acetylcholine in phenylephrine contracted intact aorta, and these effects were prevented by co-incubation with quercetin, isorhamnetin or chelerythrine (protein kinase C (PKC) inhibitor). This endothelial dysfunction was also improved by superoxide dismutase (SOD), apocynin (NADPH oxidase inhibitor) and sepiapterin (tetrahydrobiopterin synthesis substrate). Furthermore, ET-1 increased intracellular O(2*)(-) production in all layers of the vessel, protein expression of NADPH oxidase subunit p47(phox) without affecting p22(phox) expression and lucigenin-enhanced chemiluminescence signal stimulated by calcium ionophore A23187. All these changes were prevented by both quercetin and isorhamnetin. Moreover, apocynin, endothelium denudation and N(G)-nitro-l-arginine methylester (l-NAME, nitric oxide synthase inhibitor) suppressed the ET-1-induced increase in A23187-stimulated O(2*)(-) generation. Moreover, quercetin but not isorhamnetin, inhibited the increased PKC activity induced by ET-1. Taken together these results indicate that ET-1-induced NADPH oxidase up-regulation and eNOS uncoupling via PKC leading to endothelial dysfunction and these effects were prevented by quercetin and isorhamnetin.
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Romero
authors.forename: Rosario
authors.initials: R
authors.lastname: Jiménez
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez
authors.forename: Rocío
authors.initials: R
authors.lastname: López-Sepúlveda
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Zarzuelo
authors.forename: Francisco
authors.initials: F
authors.lastname: O'Valle
authors.forename: Antonio
authors.initials: A
authors.lastname: Zarzuelo
authors.forename: Francisco
authors.initials: F
authors.lastname: Pérez-Vizcaíno
authors.forename: Juan
authors.initials: J
authors.lastname: Duarte
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044948:Flavonols / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D019255:NADPH Oxidases / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology* / Q000031:analogs & derivatives; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism*
chemical_list: D000959:Antihypertensive Agents; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D044948:Flavonols; C047368:3-methylquercetin; D013481:Superoxides; D011794:Quercetin; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D011493:Protein Kinase C