Juan Duarte

Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats

The effects of an oral daily dose (10 mg kg−1) of the flavonoid quercetin for 5 weeks in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) were analysed. Quercetin induced a significant reduction in systolic (−18%), diastolic (−23%) and mean (−21%) arterial blood pressure and heart rate (−12%) in SHR but not in WKY rats. The left ventricular weight index and the kidney weight index in vehicle‐treated SHR were significantly greater than in control WKY and these parameters were significantly reduced in quercetin‐treated SHR in parallel with the reduction in systolic blood pressure. Quercetin had no effect on the vasodilator responses to sodium nitroprusside or to the vasoconstrictor responses to noradrenaline or KCl but enhanced the endothelium‐dependent relaxation to acetylcholine (Emax=58±5%vs 78±5%, P<0.01) in isolated aortae. The 24 h urinary isoprostane F2α excretion and the plasma malonyldialdehyde (MDA) levels in SHR rats were increased as compared to WKY rats. However, in quercetin‐treated SHR rats both parameters were similar to those of vehicle‐treated WKY. These data demonstrate that quercetin reduces the elevated blood pressure, the cardiac and renal hypertrophy and the functional vascular changes in SHR rats without effect on WKY. These effects were associated with a reduced oxidant status due to the antioxidant properties of the drug.

Vasodilatory effects of flavonoids in rat aortic smooth muscle. Structure-activity relationships

1. Flavonoids relaxed the contractions induced by noradrenaline, KCl or phorbol 12-myristate, 13-acetate in rat aortic strips, the order of potency being: flavonols (quercetin, kaempferol, pentamethylquercetin) > flavones(luteolin, apigenin) > flavanols((+)-catechin, (-)-epicatechin) which correlates with the reported order of potency to inhibit protein kinase C. 2. The relaxant effects of kaempferol and luteolin were slightly potentiated by isoprenaline and those of pentamethylquercetin, kaempferol and apigenin by sodium nitroprusside. 3. It is concluded that the main vasodilatory mechanism of flavonoids seems to be the inhibition of protein kinase C. Inhibition of cyclic nucleotide phosphodiesterases or decreased Ca2+ uptake may also contribute to their vasodilatory effects.

Quercetin downregulates NADPH oxidase, increases eNOS activity and prevents endothelial dysfunction in spontaneously hypertensive rats.

Background and 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 sponataneously hypertensive rats (SHR). Design and 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 p47phox were analysed by Western blot, eNOS activity by conversion of [3H]arginine to L-[3H]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 p47phox 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 p47phox expression appear to be essential mechanisms for the improvement of endothelial function and the antihypertensive effects of chronic quercetin.

Vasodilator effects of quercetin in isolated rat vascular smooth muscle

The effects of quercetin were studied on contractile responses induced by noradrenaline, high KCl, Ca2+ and phorbol 12-myristate,13-acetate in rat aortic strips and on spontaneous mechanical activity in rat portal vein segments. Quercetin, 10(-6)-10(-4) M, inhibited in a concentration-dependent manner the contractions induced by noradrenaline, high KCl and Ca2+, this effect being observed when the drug was added before or after the induced contractions. The spontaneous myogenic portal activity was also inhibited. Mechanical removal of endothelium did not affect the relaxant effects of quercetin on noradrenaline-induced contractions. In addition, at the same range of concentrations, quercetin also relaxed the contractions induced by phorbol 12-myristate,13-acetate. Quercetin1 10(-5) and 5 x 10(-5) M, increased the aortic cyclic AMP content. However, pretreatment with 10(-7) M isoprenaline did not modify the relaxant effects of quercetin on noradrenaline-induced contractions and quercetin did not modify the relaxant effects of forskolin, which suggested that the vasodilator effects of quercetin were not mediated by inhibition of cyclic AMP phosphodiesterases. In conclusion, in isolated rat aorta quercetin produced a vasodilator effect that seems to be mainly related to the inhibition of protein kinase C. However, and since this drug exerts multiple biochemical effects, inhibition of other transduction pathways may be involved in this effect.

Flavonols and cardiovascular disease

Flavonols, and specially quercetin, are widely distributed in plants and are present in considerable amounts in fruits and vegetables. In addition to their anti-oxidant effect, flavonols interfere with a large number of biochemical signaling pathways and, therefore, physiological and pathological processes. There is solid evidence that, in vitro, quercetin and related flavonols exert endothelium-independent vasodilator effects, protective effect on nitric oxide and endothelial function under conditions of oxidative stress, platelet antiaggregant effects, inhibition of LDL oxidation, reduction of adhesion molecules and other inflammatory markers and prevention of neuronal oxidative and inflammatory damage. The metabolites of quercetin show partial protective effects on endothelial function and LDL oxidation. Quercetin produces undisputed antihypertensive and antiatherogenic effects, prevents endothelial dysfunction and protects the myocardium from ischemic damage. It has no clear effects on serum lipid profile and on insulin resistance. Human intervention trials with isolated flavonols demonstrate an antihypertensive effect. The meta-analysis of epidemiological studies show an inverse association between flavonol (together with flavone) intake and coronary heart disease and stroke. Therefore, although there is no solid proof yet, a substantial body of evidence suggests that quercetin may prevent the most common forms of cardiovascular disease contributing to the protective effects afforded by fruits and vegetables.

Antihypertensive effects of the flavonoid quercetin

The blood pressure lowering effect of a fruit and vegetable-rich diet is a necessary dietary lifestyle measure now included the guidelines for the management of arterial hypertension. Furthermore, flavonoids represent a major class of plant polyphenolics. The present review addresses the antihypertensive effect of quercetin, one of the most abundant flavonoids present in fruits and vegetables, and probably the best studied flavonoid because of its high biological activity. Quercetin has been shown to induce a progressive, dose-dependent and sustained reduction in blood pressure when given chronically in several rat models of hypertension, including spontaneously hypertensive rats, L-NAME-treated rats, DOCA-salt hypertensive rats, two-kidney one-clip Goldblatt rats, rats with aortic constriction and Dahl salt-sensitive hypertensive rats. Quercetin was also effective in reducing blood pressure in rat models of metabolic syndrome, including the obese Zucker rats as well as rats treated with a high-sucrose, high-fat diet. Quercetin also prevented morphological and functional changes in the heart, vessels and kidney, while increasing production of reactive oxygen species associated with hypertension. A high dose of quercetin also reduced blood pressure in stage 1 hypertensive patients in a randomized, double-blind, placebo-controlled, crossover study. Since raised blood pressure is the major cause of stroke as well as an important risk factor for ischemic heart disease, we propose that the blood pressure-lowering effect of quercetin could be an important mechanism contributing to the reduced risk of myocardial infarction and stroke observed with fruit and vegetables-rich diets, and possibly with flavonoid-rich diets.

Endothelial function and cardiovascular disease: Effects of quercetin and wine polyphenols

Endothelial dysfunction is an early pathophysiological feature and independent predictor of poor prognosis in most forms of cardiovascular diseases. Epidemiological studies report an inverse association between dietary flavonoid consumption and mortality from cardiovascular diseases. In the present paper, we review the effects of flavonoids, especially quercetin and wine polyphenols, on endothelial function and dysfunction and its potential protective role in hypertension, ischemic heart disease and stroke. In vitro studies show that flavonoids may exert multiple actions on the NO-guanylyl cyclase pathway, endothelium-derived hyperpolarizing factor(s) and endothelin-1 and protect endothelial cells against apoptosis. In vivo, flavonoids prevent endothelial dysfunction and reduce blood pressure, oxidative stress and end-organ damage in hypertensive animals. Moreover, some clinical studies have shown that flavonoid-rich foods can improve endothelial function in patients with hypertension and ischemic heart disease. Altogether, the available evidence indicates that quercetin and wine polyphenols might be of therapeutic benefit in cardiovascular diseases even though prospective controlled clinical studies are still lacking.

Protective effects of the flavonoid quercetin in chronic nitric oxide deficient rats

Objectives The present study analysed, for the first time, the effects of the flavonoid quercetin in rats after chronic inhibition of nitric oxide (NO) synthesis with Nω-nitro-l-arginine methyl ester (l-NAME). Design Rats were divided randomly into five different treatment groups for 6 weeks: (1) vehicle (control, 1 ml of 1% methylcellulose once daily); (2) vehicle plus l-NAME (75 mg/100 ml in drinking water); (3) quercetin (10 mg/kg p.o. once daily); (4) quercetin (5 mg/kg p.o.) plus l-NAME; and (5) quercetin (10 mg/kg p.o.) plus l-NAME. Methods The evolution of systolic blood pressure, morphological variables, proteinuria, plasma malondialdehyde and nitrite and nitrate concentrations, hepatic glutathione and malondialdehyde content, glutathione enzymes activity and vascular reactivity at the end of the experiment were analysed. Results Quercetin markedly inhibited the development of l-NAME-induced hypertension. This effect was accompanied by a partial or full prevention of most of the effects induced by l-NAME, such as: (1) increases in the left ventricular and kidney weight indices; (2) proteinuria; (3) renal histological lesions, including hyaline arteriopathy and thickening of the vascular wall with moderate decrease of the lumen; (4) increased endothelium-dependent contraction; (5) increased vascular thromboxane B2 (TXB2) synthesis; (6) reduced plasma concentrations of nitrites plus nitrates (NOx); (7) increased plasma and hepatic malondialdehyde (MDA) concentrations; and (8) reduced glutathione peroxidase activity. In most cases these effects were dose dependent, but none of them were observed in normotensive animals. Conclusions This study confirms and extends the previous evidence about the antihypertensive effects and end-organ protection of the flavonoid quercetin in animal models of hypertension.

Effects of flavonoids on rat aortic smooth muscle contractility: structure-activity relationships.

1. Flavonoids produced a concentration-dependent relaxation of the contractile responses induced by noradrenaline, KCl, or phorbol 12-myristate-13-acetate in rat aortic rings. Only the flavonoid with three contiguous hydroxyls in B rings (myricetin), at low concentrations, potentiates the contractions evoked by these agonists. 2. The relaxant effects of flavanone on the noradrenaline-induced contractions were potentiated by isoprenaline and those of morin, chrysin, flavanone, and naringenin by sodium nitroprusside. 3. Several mechanisms are implicated in the vasodilatory effects of flavonoids: inhibition of protein kinase C; inhibition of cyclic nucleotide phosphodiesterases; and/or decreased Ca2+ uptake.

Quercetin inhibits vascular superoxide production induced by endothelin-1: Role of NADPH oxidase, uncoupled eNOS and PKC

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.