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.

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These data substantiate CNP/NPR-C signalling as a fundamental pathway underlying EDHF-dependent regulation of vascular tone in the rat mesenteric resistance vasculature. An increased understanding of the physiological roles of CNP/NPR-C signalling in the vasculature (now facilitated by the identification of a selective NPR-C antagonist) should aid determination of the (patho)physiological importance of EDHF and might provide the rationale for the design of novel therapeutics.

The dietary flavonoid quercetin reduces blood pressure and improves endothelial function in several rat models of hypertension. We analyzed the effects of quercetin and its methylated metabolite isorhamnetin on the aortic endothelial dysfunction induced by incubation with angiotensin II (AngII) in vitro for 6 h. AngII diminished the relaxant responses to acetylcholine in phenylephrine-contracted aorta. Coincubation with quercetin or isorhamnetin, or addition of superoxide (O(2)(-)) dismutase or apocynin to the assay medium, prevented these inhibitory effects. At 6 h, AngII induced a marked increase in O(2)(-) production as measured by dihydroethidium fluorescence, which was prevented by quercetin and isorhamnetin. AngII also increased the expression of p47(phox), a regulatory subunit of the membrane NADPH oxidase. Immunohistochemical analysis revealed that overexpression of p47(phox) occurred mainly in the medial layer. p47(phox) overexpression was also prevented by quercetin and isorhamnetin. Taken together, these results show for the first time, to our knowledge, that quercetin and isorhamnetin prevent AngII-induced endothelial dysfunction by inhibiting the overexpression of p47(phox) and the subsequent increased O(2)(-) production, resulting in increased nitric oxide bioavailability.

The aims of the present study were to analyse the effects of an oral daily dose (10 mg/kg) of the dietary flavonoid quercetin for five weeks in two-kidney, one-clip (2K1C) Goldblatt (GB) hypertensive rats. The evolution of systolic blood pressure was followed by weekly measurements, and morphological variables, proteinuria, plasma nitrates plus nitrites (NOx) and thiobarbituric acid reactive substances (TBARS), liver oxidative stress markers and endothelial function were determined at the end of the experimental period. Quercetin treatment reduced systolic blood pressure of GB rats, producing no effect in control animals. It also reduced cardiac hypertrophy and proteinuria developed in GB hypertensive rats. Decreased endothelium-dependent relaxation to acetylcholine of aortic rings from GB rats was improved by chronic quercetin treatment, as well as increased endothelium-dependent vasoconstrictor response to acetylcholine and overproduction of TXB2 by aortic vessels of GB rats, being without effect in normotensive animals. Increased plasma NOx and TBARS, and decreased liver total glutathione (GSH) levels and glutathione peroxidase (GPX) activity were observed in GB hypertensive rats compared to the control animals. Normalisation of plasma NOx and TBARS concentrations and improvement of the antioxidant defences system in liver accompanied the antihypertensive effect of quercetin. We conclude that chronic oral treatment with quercetin shows both antihypertensive and antioxidant effects in this model of renovascular hypertension.