Quercetin downregulates NADPH oxidase, increases eNOS activity and prevents endothelial dysfunction in spontaneously hypertensive rats.
OBJECTIVE
Several studies have found that chronic treatment with the dietary flavonoid quercetin lowers blood pressure and restores endothelial dysfunction in hypertensive animal models. We hypothesized that increased endothelial nitric oxide synthase (eNOS) and/or decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase protein expression and activity, and reduced reactive oxygen species might be involved in the improvement of endothelial function induced by quercetin in spontaneously hypertensive rats (SHR).


METHODS
Male SHR and Wistar-Kyoto (WKY) rats (5 weeks old) were treated with quercetin (10 mg/kg) or vehicle for 13 weeks. Changes in vascular expression of eNOS, caveolin-1 and p47 were analysed by Western blot, eNOS activity by conversion of [H]arginine to L-[H]citrulline, and NADPH oxidase activity by NADPH-enhanced chemoluminescence of lucigenin.


RESULTS
In SHR, quercetin reduced the increase in blood pressure and heart rate and enhanced the endothelium-dependent aortic vasodilation induced by acetylcholine, but had no effect on the endothelium-independent response induced by nitroprusside. However, quercetin had no effect on endothelium-dependent vasoconstriction and aortic thromboxane B2 production. Compared to WKY, SHR showed upregulated eNOS and p47 protein expression, downregulated caveolin-1 expression, increased NADPH-induced superoxide production but, paradoxically, eNOS activity was reduced. Chronic quercetin treatment prevented all these changes in SHR. In WKY, quercetin had no effect on blood pressure, endothelial function or the expression or activity of the proteins analysed.


CONCLUSIONS
Enhanced eNOS activity and decreased NADPH oxidase-mediated superoxide anion (O2) generation associated with reduced p47 expression appear to be essential mechanisms for the improvement of endothelial function and the antihypertensive effects of chronic quercetin.
Sánchez
Manuel
M
Department of Pharmacology, School of Pharmacy, University of Granada, Granada, Spain.
Galisteo
Milagros
M
Vera
Rocío
R
Villar
Inmaculada C
IC
Zarzuelo
Antonio
A
Tamargo
Juan
J
Pérez-Vizcaíno
Francisco
F
Duarte
Juan
J
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D051242:Caveolin 1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000201:enzymology* / Q000503:physiopathology*; D008163:Luminescent Measurements; D008297:Male; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism; D013895:Thoracic Arteries / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D013929:Thromboxane B2 / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D000959:Antihypertensive Agents; D051242:Caveolin 1; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D013929:Thromboxane B2; D011794:Quercetin; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D000109:Acetylcholine