Félix Vargas

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.

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 chronic quercetin treatment in experimental renovascular hypertension.

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. (Mol Cell Biochem 270: 147–155, 2005)

Wine Polyphenols Improve Endothelial Function in Large Vessels of Female Spontaneously Hypertensive Rats

Red wine polyphenols (RWPs) have been reported to prevent hypertension and endothelial dysfunction. Several individual RWPs exert estrogenic effects. We analyzed the possible in vivo protective effects on blood pressure and endothelial function of RWPs in female spontaneously hypertensive rats (SHR) and its relationship with ovarian function. RWPs (40 mg/kg by gavage) were orally administered for 5 weeks. Ovariectomized rats showed both increased isoprostaglandin F2&agr; excretion and aortic superoxide production and reduced relaxant response to acetylcholine and contraction to the endothelial nitric oxide synthase (eNOS) inhibitor l-NAME measured in the aorta but similar blood pressure, as compared with sham-operated rats. Moreover, in ovariectomized rats aortic eNOS expression was unchanged, whereas caveolin-1, angiotensin II receptor (AT)-1, and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p22phox and p47phox expression was increased compared with sham-operated rats. In both ovariectomized and sham-operated SHR, RWPs reduced systolic blood pressure, urinary isoprostaglandin F2&agr; excretion, and aortic O2− production, improving the endothelium-dependent relaxant response to acetylcholine in SHR. These changes were associated with unchanged aortic eNOS expression, whereas caveolin-1 was increased and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p22phox and p47phox expression was reduced. RWPs had no effect on the AT-1 overexpression found in ovariectomized animals. All these results suggest that a chronic treatment with RWPs reduces hypertension and vascular dysfunction through reduction in vascular oxidative stress in female SHR in a manner independent of the ovarian function.

Epicatechin lowers blood pressure, restores endothelial function, and decreases oxidative stress and endothelin-1 and NADPH oxidase activity in DOCA-salt hypertension.

Flavanol-rich diets have been reported to exert beneficial effects in preventing cardiovascular diseases, such as hypertension. We studied the effects of chronic treatment with epicatechin on blood pressure, endothelial function, and oxidative status in deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Rats were treated for 5 weeks with (-)-epicatechin at 2 or 10 mg kg(-1)day(-1). The high dose of epicatechin prevented both the increase in systolic blood pressure and the proteinuria induced by DOCA-salt. Plasma endothelin-1 and malondialdehyde levels and urinary iso-prostaglandin F(2α) excretion were increased in animals of the DOCA-salt group and reduced by the epicatechin 10 mg kg(-1) treatment. Aortic superoxide levels were enhanced in the DOCA-salt group and abolished by both doses of epicatechin. However, only epicatechin at 10 mg kg(-1) reduced the rise in aortic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and p47(phox) and p22(phox) gene overexpression found in DOCA-salt animals. Epicatechin increased the transcription of nuclear factor-E2-related factor-2 (Nrf2) and Nrf2 target genes in aortas from control rats. Epicatechin also improved the impaired endothelium-dependent relaxation response to acetylcholine and increased the phosphorylation of both Akt and eNOS in aortic rings. In conclusion, epicatechin prevents hypertension, proteinuria, and vascular dysfunction. Epicatechin also induced a reduction in ET-1 release, systemic and vascular oxidative stress, and inhibition of NADPH oxidase activity.

Effects of chronic quercetin treatment on antioxidant defence system and oxidative status of deoxycorticosterone acetate-salt-hypertensive rats

We investigated the potential of chronic administration of an oral daily dose (10 mg/kg) of the dietary flavonoid quercetin to prevent hypertension and oxidative stress induced by deoxycorticosterone acetate (DOCA)-salt in rats. We have compared its effects to those produced by the well-known anti-hypertensive drug verapamil, administered orally (20 mg/kg/day). Quercetin and verapamil treatments reduced systolic blood pressure of DOCA-salt rats in approximately 67.6 and 63.3% respectively, producing no effect in control animals. Both drugs reduced significantly hepatic and renal hypertrophy induced by DOCA-salt administration, while only quercetin prevented cardiac hypertrophy. Decreased endothelium-dependent relaxation to acetylcholine of aortic rings from DOCA-salt-treated rats was improved by quercetin, but verapamil only enhanced it in the presence of superoxide dismutase (SOD) plus catalase. Increased plasma and heart thiobarbituric acid reactive substances (TBARS) and total glutathione (GSH) levels in liver and heart, decreased liver glutathione peroxidase (GPX) and liver and kidney glutathione transferase (GST) activities were observed in DOCA-salt-treated rats compared to the control animals. The antihypertensive effect of quercetin was accompanied by normalisation of plasma TBARS values, improvement of the antioxidant defences system in heart and liver, restoring total GSH levels in both organs and altered liver GST and GPX activities, and improving kidney GST activity. Verapamil treatment only restored GSH levels in heart, having no effect on other alterations induced by DOCA-salt chronic administration in the antioxidant defences analysed. In conclusion, quercetin shows both antihypertensive and antioxidant properties in this model of mineralocorticoid hypertension, while verapamil exhibits only antihypertensive effects.

Activation of peroxisome proliferator-activated receptor-β/-δ (PPARβ/δ) prevents endothelial dysfunction in type 1 diabetic rats.

Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. Herein, we have analyzed if the peroxisome proliferator-activated receptor-β/-δ (PPARβ/δ) agonist GW0742 exerts protective effects on endothelial function in type 1 diabetic rats. The rats were divided into 4 groups: control, control-treated (GW0742, 5 mg kg(-1)day(-1) for 5 weeks), diabetic (streptozotocin injection), and diabetic-treated. GW0742 administration in diabetic rats did not alter plasma glucose, systolic blood pressure, or heart rate, but reduced plasma triglyceride levels. The vasodilatation induced by acetylcholine was decreased in aortas from diabetic rats. GW0742 restored endothelial function, increasing eNOS phosphorylation. Superoxide production, NADPH oxidase activity, and mRNA expression of prepro endothelin-1, p22(phox), p47(phox), and NOX-1 were significantly higher in diabetic aortas, and GW0742 treatment prevented these changes. In addition, GW0742 prevented the endothelial dysfunction and the upregulation of prepro endothelin-1 and p47(phox) after the in vitro incubation of aortic rings with high glucose and these effects were prevented by the PPARβ/δ antagonist GSK0660. PPARβ/δ activation restores endothelial function in type 1 diabetic rats. This effect seems to be related to an increase in nitric oxide bioavailability as a result of reduced NADPH oxidase-driven superoxide production and downregulation of prepro endothelin-1.

Effects of chronic increased salt intake on nitric oxide synthesis inhibition-induced hypertension

Objective and method Experimental evidence suggests that endogenous nitric oxide plays an important role in the homeostatic response to an increase in sodium intake. In the present study we evaluated the influence of a high sodium intake (1% NaCl as drinking water) on arterial hypertension induced by long-term (6–7 weeks) inhibition of nitric oxide synthesis [NG-nitro-L-arginine methyl ester (L-NAME), 75 mg/100 ml in the drinking fluid] in rats. Results Treatment with L-NAME induced progressive elevations in tail-cuff systolic blood pressure, but there were no differences between rats drinking tap water and rats drinking 1% NaCl. Direct measurement of blood pressure at the end of the treatment confirmed the hypertension and the lack of differences between the two groups treated with L-NAME. Metabolic studies performed at the end of L-NAME treatment showed a reduced glomerular filtration rate and elevated urinary excretion of immunoreactive endothelin in the two hypertensive groups treated with L-NAME. Drinking intake, diuresis and natriuresis were significantly higher only in the L-NAME group drinking 1% NaCI. Both groups treated with L-NAME showed an accelerated and increased diuretic and natriuretic response to an isotonic 0.9% NaCl load (2.5 ml/100 g body weight, intraperitoneally). At the end of the study ventricular hypertrophy was observed in both L-NAME groups. Conclusion The present results indicate that the time-dependent elevation in blood pressure produced by long-term inhibition of nitric oxide production is not affected by an increased sodium intake. However, salt supplementation induced the development of a polyuria and polydipsia syndrome in rats treated with L-NAME. The elevated excretion of endothelin in both groups treated with L-NAME suggests the possible participation of endothelin in the development of L-NAME hypertension.

Endothelium-Dependent and Endothelium-lndependent Vasodilation in Hyperthyroid and Hypothyroid Rats

The effects of hyper- and hypothyroidism on the vasorelaxing responses to acetylcholine (ACh), sodium nitroprusside (NP), and CaCl2 were investigated in aortic strips and isolated perfused

Increased Pressor Sensitivity to Chronic Nitric Oxide Deficiency in Hyperthyroid Rats

Abstract—We studied the effects of a possible interaction between partial nitric oxide deficiency and thyroid hormone excess on the long-term control of blood pressure (BP) and morphological and renal variables and examined the role of the renin-angiotensin system in the increased BP of this interaction. Eight groups (n=8 each) of male Wistar rats were used: a control group; 3 groups that were treated with thyroxine (50 &mgr;g/d), Nw-nitro-l-arginine methyl ester (l-NAME; subpressor dose, 1.5 mg · kg−1 · d−1), or thyroxine plus l-NAME; and another 4 similarly treated groups that received losartan (20 mg · kg−1 · d−1) in their drinking fluid. All treatments were maintained for 3 weeks. The time course of tail systolic BP was recorded once a week. At the end of the experimental period, we measured mean arterial pressure in conscious rats and assessed the morphological, metabolic, plasma, and renal variables. Thyroxine produced a mild BP increase from the second week of treatment and an increase in plasma angiotensin II and plasma nitrates/nitrites by the end of the study. Simultaneous administration of thyroxine and a subpressor dose of l-NAME produced a marked BP increase that reached significance from the first week of treatment. Losartan produced normotension in thyroxine-treated rats and attenuated the BP elevation in thyroxine+l-NAME–treated rats. Hyperthyroid rats showed relative renal and ventricular hypertrophy, absence of absolute left ventricular hypertrophy, and proteinuria. These alterations were not changed by losartan. We conclude that an impaired nitric oxide system might have a counterregulatory homeostatic role against the prohypertensive effects of thyroid hormone and that the renin-angiotensin system plays an important role in thyroxine+l-NAME hypertension.