stilbenes and Hypertension

Hypertension is associated with endothelial dysfunction and decreased nitric oxide (NO). It has been proposed that decreasing oxidative stress may help regulate blood pressure by increasing NO concentration. Therefore, the purpose of this systematic review was to determine whether the antioxidant resveratrol effects NO-mediated vascular outcomes in hypertension. A comprehensive literature search of PubMed and EBSCOhost databases was conducted using the terms: "resveratrol" and "nitric oxide or NO" and "hypertension or high blood pressure." Searches were not restricted for year of publication or study design but limited to full-text studies from scholarly, peer-reviewed journals. Ten animal studies published between 2005 and 2017 were identified. Human studies did not meet criteria and were not included. Articles were critically assessed using the Academy of Nutrition and Dietetics' Evidence Analysis Library Quality Criteria Worksheet. All studies evaluated resveratrol supplementation and at least one NO outcome measure including: circulating NO metabolites, endothelial nitric oxide synthase (eNOS) expression, eNOS phosphorylation, and eNOS uncoupling. All but one study assessed blood pressure. Nine of ten studies reported positive significant results of resveratrol supplementation on NO outcomes, and in all but one study, this was seen concomitantly with decreases in blood pressure. Resveratrol supplementation shows promise for improving NO-mediated vascular outcomes and improving blood pressure. Translation to human studies is warranted, with dose of resveratrol considered, as the human equivalency doses are not consistent amongst animal studies. Additionally, a standard battery of tests examining NO-mediated vascular outcomes is needed to ensure generalizability among studies to determine dose-duration effects.

Topics: Animals; Antioxidants; Dietary Supplements; Endothelium, Vascular; Humans; Hypertension; Nitric Oxide; Nitric Oxide Synthase Type III; Resveratrol; Stilbenes

Aging is a major risk factor for the development of cardiovascular disease. Despite a significant reduction in the mortality and morbidity rates over the last decade, the socio-economic burden of cardiovascular disease is still substantial. Consequently, there is a considerable need for alternative strategies, such as nutraceutical supplementation, that delay the functional vascular decline present in the elderly. Compromised autophagy and oxidative stress (OS) are considered major causes of the age-related endothelial dysfunction. OS reduces the bioavailability of nitric oxide (NO), which has been associated with hypertension, arteriosclerosis, and a reduced vasodilatory response. High levels of free radicals and the low bioavailability of NO lead to a positive feedback loop of further OS, organelle damage, poor repair, and endothelial dysfunction. Here we draw attention to the relationship between OS and autophagy in the aged vasculature. We have reviewed the published literature and provided arguments that support that treatment with resveratrol stimulates autophagy and thereby has the potential to restore oxidative balance in the endothelium, which indicates that treatment with resveratrol might have therapeutic potential to restore endothelial function in the elderly.

Topics: Aging; Animals; Antioxidants; Arteriosclerosis; Autophagy; Endothelium, Vascular; Humans; Hypertension; Nitric Oxide; Oxidative Stress; Resveratrol; Stilbenes

Beyond the well-known effects on blood pressure (BP) of the dietary approaches to stop hypertension (DASH) and the Mediterranean diets, a large number of studies has investigated the possible BP lowering effect of different dietary supplements and nutraceuticals, the most part of them being antioxidant agents with a high tolerability and safety profile. In particular relatively large body of evidence support the use of potassium, L-arginine, vitamin C, cocoa flavonoids, beetroot juice, coenzyme Q10, controlled-release melatonin, and aged garlic extract. However there is a need for data about the long-term safety of a large part of the above discussed products. Moreover further clinical research is advisable to identify between the available active nutraceuticals those with the best cost-effectiveness and risk-benefit ratio for a large use in general population with low-added cardiovascular risk related to uncomplicated hypertension.

Topics: Amino Acids; Beta vulgaris; Blood Pressure; Carotenoids; Clinical Trials as Topic; Dietary Supplements; Fatty Acids, Unsaturated; Flavonoids; Fruit and Vegetable Juices; Garlic; Humans; Hypertension; Lycopene; Magnesium; Melatonin; Meta-Analysis as Topic; Minerals; Peptides; Plant Extracts; Potassium; Probiotics; Proteins; Resveratrol; Stilbenes; Ubiquinone; Vitamins

We review evidence for and against the 'red wine hypothesis', whereby red wine is more likely to confer cardiovascular benefits than white. As background, there is a strong epidemiological and mechanistic evidence for J-shaped relation between alcohol intake and total mortality. However, epidemiological data favouring a specific benefit of red over white wine are not strong and the 'French paradox' could at least in part be explained by confounding factors. More convincing evidence is that human studies with de-alcoholized red but not white wine show short-term cardiovascular benefits. The specific components of the de-alcoholized wine that are active on cardiovascular endpoints, are the polyphenols found in red wine, especially resveratrol. The effects of resveratrol on isolated tissues or organs are well-described including molecular mechanisms leading to decreased arterial damage, decreased activity of angiotensin-II, increased nitric oxide, and decreased platelet aggregation. Anti-ischaemic effects include stimulation of prosurvival paths, decreased LDL-oxidation, atheroma, and on the ischaemic-beneficial metabolic changes. Most recently, the agonist effect of resveratrol on the anti-senescence factor sirtuin has lessened cell death in myocytes from failing hearts. Mechanistic feasibility strengthens the case for prospective therapeutic trials of alcohol vs. red wine vs. resveratrol, for example in those with heart failure.

Topics: Alcohol Drinking; Animals; Arteriosclerosis; Coronary Disease; Female; Flavonoids; Humans; Hypertension; Male; Mice; Phenols; Platelet Aggregation; Platelet Aggregation Inhibitors; Polyphenols; Rats; Resveratrol; Risk Factors; Stilbenes; Wine

Endothelial dysfunction is a surrogate marker of cardiovascular risk. Resveratrol is known to improve endothelial function in animals, however, clinical trials are limited. We hypothesized that the acute trans-resveratrol supplementation improves endothelial function in treated hypertensive patients with endothelial dysfunction. Twenty-four hypertensive patients between 45 and 65 years-old with baseline endothelial dysfunction were enrolled in a randomized, cross-over, double-blind, placebo-controlled trial. Individuals received either a single dose of trans-resveratrol (300 mg) or placebo and were crossed-over after a one-week washout period. Blood pressure (BP) measurements, aortic systolic blood pressure (SBP) and brachial flow-mediated dilation (FMD) were performed before and 1.5 hours after the intervention. FMD was significantly increased in women (4.2 ± 0.5 vs 7.1 ± 1.3%, p = 0.026) but not in men (4.4 ± 0.9 vs 4.9 ± 0.8%, p = 0.588) in the trans-resveratrol group. There was no statistical difference between baseline and final values of brachial BP and also no changes in aortic SBP. Patients with higher low-density lipoprotein (LDL) cholesterol had better FMD response to trans-resveratrol than patients with lower LDL cholesterol (7.4 ± 1.2 vs 4.3 ± 1.0%, p = 0.004). Our study demonstrated that the acute supplementation of trans-resveratrol promoted an improvement in endothelial function, especially in women and those with higher LDL-cholesterol, despite no changes in BP. List of Abbreviation: Aix: augmentation index; AP: augmentation pressure; BP: blood pressure; BMI: body Mass Index; CVD: cardiovascular disease; FMD: flow-mediated dilation; FRS: Framingham Risk Score; HDL: high-density lipoprotein; LDL: low-density lipoprotein; NO: nitric oxide; SPSS: Statistical Package for Social Sciences; ROS: reactive oxygen species; SBP: systolic blood pressure; TG: triglycerides.

Topics: Antioxidants; Aorta; Blood Pressure; Brachial Artery; Cholesterol, LDL; Cross-Over Studies; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Resveratrol; Sex Factors; Stilbenes; Vasodilation

Isolated phytochemicals have been shown to reduce blood pressure; however, combinations of phytochemicals have rarely been tested in humans. We hypothesized that a combination of extracts from grape seed and skin (330 mg), green tea (100 mg), resveratrol (60 mg) and a blend of quercetin, ginkgo biloba and bilberry (60 mg) would reduce blood pressure (BP) in hypertensive subjects.. Eighteen individuals meeting BP requirements (⩾130 mm Hg systolic or ⩾85 mm Hg diastolic) and criteria for metabolic syndrome were enrolled in a double-blinded, placebo-controlled, crossover trial (ClinicalTrials.gov, NCT01106170). The 28-day placebo and supplement arms were separated by a 2-week washout period, and 14 -h daytime ambulatory BP was assessed at baseline and at the end point of each arm.. BP was not altered after placebo. After supplement treatment, diastolic pressure was reduced by 4.4 mm Hg (P=0.024, 95% CI, 0.6-8.1), systolic pressure was unchanged and mean arterial pressure trended (P=0.052) toward reduction. Serum angiotensin-converting enzyme activity was similar between placebo and supplement arms, but urinary nitrate and nitrite concentrations were significantly increased (P=0.022) after supplementation. Human aortic endothelial cells treated with metabolites of the polyphenols used in the human supplement trial had a significant increase (P=0.005) in insulin-stimulated eNOS phosphorylation and greater (P<0.001) accumulation of nitrates/nitrites.. Our clinical and in vitro data support the theory that this combination of polyphenols reduced diastolic pressure by potentiating eNOS activation and nitric oxide production. Such supplements may have clinical relevance as stand-alone or adjunct therapy to help reduce BP.

Topics: Adult; Antihypertensive Agents; Antioxidants; Blood Pressure; Cross-Over Studies; Dietary Supplements; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hypertension; Magnoliopsida; Male; Metabolic Syndrome; Middle Aged; Nitric Oxide; Nitric Oxide Synthase Type III; Phytochemicals; Phytotherapy; Plant Extracts; Polyphenols; Quercetin; Resveratrol; Stilbenes

Hypertension is a global health concern for which novel treatment strategies are necessary. The aim of this study is to evaluate the efficacy of resveratrol (trans-3, 5, 4'-trihydroxystilbene, a polyphenol present in grapes) in controlling blood pressure in participants diagnosed with prehypertension and stage 1 hypertension.. In a randomized, crossover, double-blinded, placebo-controlled study, 50 participants with prehypertension (diastolic blood pressure and systolic blood pressure, 80-89 mmHg and 120-139 mmHg, respectively) and 50 participants with stage 1 hypertension (diastolic and systolic, 90-99 mmHg and 140-159 mmHg, respectively) will be assigned to receive resveratrol (99 % pure, from Biotivia Longevity Bioceuticals LLC Company, USA, in 500 mg capsules, twice daily for 4 weeks, orally) or placebo (500 mg neutral microcellulose capsules, twice daily for 4 weeks) in a 2 × 2 crossover design (4 weeks treatment-4 weeks washout-4 weeks treatment). The blood pressure of each participant will be recorded (a mean of two times within a 15-minute interval) every week during the study. The participants in the prehypertensive group will not receive any medication, while those in the stage 1 hypertensive group will continue to receive their routine medications during the study. Blood samples will be taken from all groups and examined for various biochemical parameters.. This trial will help to establish whether resveratrol is an effective antihypertensive agent in prehypertensive and stage 1-hypertensive patients. The trial outcome will provide novel insight into the clinical efficacy of resveratrol and provide valuable information for conducting future clinical studies with resveratrol.. Iranian Registry of Clinical Trials, IRCT201407078129N7. Registered on 15 August 2014.

Topics: Clinical Protocols; Cross-Over Studies; Double-Blind Method; Humans; Hypertension; Outcome Assessment, Health Care; Resveratrol; Sample Size; Stilbenes

Numerous studies have shown that resveratrol (RES) exerts anti-inflammatory effects but human trials evidencing these effects in vivo are limited. Furthermore, the molecular mechanisms triggered in humans following the oral intake of RES are not yet understood. Therefore, the purpose of this study was to investigate the molecular changes in peripheral blood mononuclear cells (PBMCs) associated to the one-year daily intake of a RES enriched (8 mg) grape extract (GE-RES) in hypertensive male patients with type 2 diabetes mellitus (T2DM). We used microarrays and RT-PCR to analyze expression changes in genes and microRNAs (miRs) involved in the inflammatory response modulated by the consumption of GE-RES in comparison to a placebo and GE lacking RES. We also examined the changes in several serobiochemical variables, inflammatory and fibrinolytic markers. Our results showed that supplementation with GE or GE-RES did not affect body weight, blood pressure, glucose, HbA1c or lipids, beyond the values regulated by gold standard medication in these patients. We did not find either any significant change on serum inflammatory markers except for a significant reduction of ALP and IL-6 levels. The expression of the pro-inflammatory cytokines CCL3, IL-1β and TNF-α was significantly reduced and that of the transcriptional repressor LRRFIP-1 increased in PBMCs from patients taking the GE-RES extract. Also, a group of miRs involved in the regulation of the inflammatory response: miR-21, miR-181b, miR-663, miR-30c2, miR-155 and miR-34a were found to be highly correlated and altered in the group consuming the GE-RES for 12 months. Our results provide preliminary evidence that long-term supplementation with a grape extract containing RES downregulates the expression of key pro-inflammatory cytokines with the involvement of inflammation-related miRs in circulating immune cells of T2DM hypertensive medicated patients and support a beneficial immunomodulatory effect in these patients.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Coronary Artery Disease; Cytokines; Diabetes Mellitus, Type 2; Dietary Supplements; Gene Expression Regulation; Humans; Hypertension; Inflammation; Leukocytes, Mononuclear; Male; MicroRNAs; Middle Aged; Models, Molecular; Plant Extracts; Resveratrol; Stilbenes; Transcriptome; Vitis

This study was designed to assess the safety, tolerability, and efficacy of intravenous infusion of CA4P in patients with neovascular age-related macular degeneration (AMD).. Prospective, interventional, dose-escalation clinical trial. Eight patients with neovascular AMD refractory to at least 2 sessions of photodynamic therapy received CA4P at a dose of 27 or 36 mg/m2 as weekly intravenous infusion for 4 consecutive weeks. Safety was monitored by vital signs, ocular and physical examinations, electrocardiogram, routine laboratory tests, and collection of adverse events. Efficacy was assessed using retinal fluorescein angiography, optical coherence tomography, and best corrected visual acuity (BCVA).. The most common adverse events were elevated blood pressure (46.7%), QTc prolongation (23.3%), elevated temperature (13.3%), and headache (10%), followed by nausea and eye injection (6.7%). There were no adverse events that were considered severe in intensity and none resulted in discontinuation of treatment. There was reduction of the excess foveal thickness by 24.15% at end of treatment period and by 43.75% at end of the two-month follow-up (p = 0.674 and 0.161, respectively). BCVA remained stable throughout the treatment and follow-up periods.. The safety profile of intravenous CA4P was consistent with that reported in oncology trials of CA4P and with the class effects of vascular disruptive agents; however, the frequency of adverse events was different. There are evidences to suggest potential efficacy of CA4P in neovascular AMD. However, the level of systemic safety and efficacy indicates that systemic CA4P may not be suitable as an alternative monotherapy to current standard-of-care therapy.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Choroidal Neovascularization; Female; Fever; Headache; Humans; Hypertension; Infusions, Intravenous; Long QT Syndrome; Macular Degeneration; Male; Middle Aged; Pilot Projects; Stilbenes; Treatment Outcome

Flow-mediated dilatation of the brachial artery (FMD) is a biomarker of endothelial function and cardiovascular health. Impaired FMD is associated with several cardiovascular risk factors including hypertension and obesity. Various food ingredients such as polyphenols have been shown to improve FMD. We investigated whether consuming resveratrol, a polyphenol found in red wine, can enhance FMD acutely and whether there is a dose-response relationship for this effect.. 19 overweight/obese (BMI 25-35 kg m(-2)) men or post-menopausal women with untreated borderline hypertension (systolic BP: 130-160 mmHg or diastolic BP: 85-100 mmHg) consumed three doses of resveratrol (resVida™ 30, 90 and 270 mg) and a placebo at weekly intervals in a double-blind, randomized crossover comparison. One hour after consumption of the supplement, plasma resveratrol and FMD were measured. Data were analyzed by linear regression versus log(10) dose of resveratrol. 14 men and 5 women (age 55 ± 2 years, BMI 28.7 ± 0.5 kg m(-2), BP 141 ± 2/89 ± 1 mmHg) completed this study. There was a significant dose effect of resveratrol on plasma resveratrol concentration (P < 0.001) and on FMD (P < 0.01), which increased from 4.1 ± 0.8% (placebo) to 7.7 ± 1.5% after 270 mg resveratrol. FMD was also linearly related to log(10) plasma resveratrol concentration (P < 0.01).. Acute resveratrol consumption increased plasma resveratrol concentrations and FMD in a dose-related manner. This effect may contribute to the purported cardiovascular health benefits of grapes and red wine.

Topics: Brachial Artery; Cardiovascular Diseases; Cross-Over Studies; Dietary Supplements; Dose-Response Relationship, Drug; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Obesity; Overweight; Placebos; Resveratrol; Risk Factors; Stilbenes; Vasodilation

Resveratrol is known to improve endothelial function in animals, but little is known about its effect on human subjects. Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors underlying endothelial dysfunction. We hypothesized that the modified resveratrol, Longevinex, improves endothelial function in patients with MetS. Thirty-four patients who had been treated for MetS and lifestyle-related disease were randomly assigned to group A, in which Longevinex was administered for 3 months and then discontinued for 3 months, whereas in the time-matched group B, Longevinex was administered between 3 and 6 months. These 2 groups of patients received similar drugs at baseline for diabetes mellitus, dyslipidemia, or hypertension. Flow-mediated dilatation significantly increased during the administration of Longevinex but decreased to baseline 3 months after the discontinuation of Longevinex in the group A patients. Conversely, in the group B patients, flow-mediated dilatation remained unchanged for the first 3 months without Longevinex but was significantly increased 3 months after the treatment with Longevinex. Longevinex did not significantly affect blood pressure, insulin resistance, the lipid profile or inflammatory markers during 6-month follow-up. These results demonstrate that Longevinex specifically improves endothelial function in subjects with MetS who were receiving standard therapy for lifestyle-related disease.

Topics: Aged; Diabetes Mellitus; Drug Compounding; Endothelium, Vascular; Female; Humans; Hyperlipidemias; Hypertension; Insulin Resistance; Life Style; Male; Metabolic Syndrome; Middle Aged; Resveratrol; Stilbenes; Vasodilation; Vasodilator Agents

The regulatory mechanisms of hypertension in youth are incompletely understood. We aimed to identify potential serum metabolic alterations associated with hypertension in adolescents. A 1:1 age- and sex-matched case-control study including 30 hypertensive adolescents aged 12-17 years and 30 normotensive adolescents for the training set and 14 hypertensive adolescents and 14 normotensive adolescents for the test set was performed, which came from one cross-sectional study in Ningxia, China. Hypertension was defined based on blood pressure (BP) values measured on three different occasions according to the BP reference of Chinese children and adolescents. Untargeted ultra-high-performance liquid tandem chromatography quadrupole time of flight mass spectrometry was used to identify differential metabolites between hypertensive and normotensive adolescents. A total of 77 metabolites in positive mode and 101 in negative mode were identified (VIP > 1.0 and P < 0.05). After adjustment for the false discovery rate, 4 differential metabolites in positive mode and 10 in negative mode were found (Q value < 0.05). The logistic regression model adjusted for body mass index and lipid profile selected four significant metabolites (4-hydroxybutanoic acid, L-serine, acetone, and pterostilbene). The main metabolic pathways of amino acid metabolism, pantothenate and CoA biosynthesis, glyoxylate and dicarboxylate metabolism, fructose and mannose metabolism, and linoleic acid metabolism may contribute to the development of hypertension in Chinese adolescents. Based on the receiver operating characteristic plot, 4-hydroxybutanoic acid, L-serine, acetone, and pterostilbene may preliminarily help distinguish hypertension from normal BP in adolescents, with AUC values of 0.857 in the training set and 0.934 in the test set. The identified metabolites and pathways may foster a better understanding of hypertension pathogenesis in Chinese adolescents.

Topics: Acetone; Adolescent; Amino Acids; Biomarkers; Case-Control Studies; Child; China; Chromatography, High Pressure Liquid; Coenzyme A; Cross-Sectional Studies; Fructose; Glyoxylates; Humans; Hypertension; Linoleic Acid; Mannose; Metabolomics; Serine; Stilbenes

Hypertension in obesity has become a major threat for public health. Omentin-1, a novel adipokine, is down-regulated in obesity. Tetrahydroxystilbene glycoside (TSG) is the main ingredient extracted from Polygonum multiflorum Thunb (PMT), a traditional Chinese medicinal herb safely used for protecting cardiovascular systems over bimillennium. This study aims to examine (i) the impact of omentin-1 downregulation on obesity-related hypertension in murine models and the underlying mechanisms; (ii) whether tetrahydroxystilbene glycoside (TSG) improved endothelial dysfunction and obesity-associated hypertension via the increase of omentin-1.. (TSG-treated) male Zucker diabetic fatty (ZDF) rats and omentin-1 knockout (OMT. Down-regulation of omentin-1 induces endothelial dysfunction and hypertension in obesity. TSG treatment (at least partially) increases omentin-1 via promoting binding of PPAR-γ and Itln-1 promoter in adipose tissues, subsequently exerts protective effects on endothelial function via activating Akt/eNOS/NO signaling and attenuating oxidative/nitrative stress. These results suggest that TSG could be developed as a promising anti-hypertension agent that protects against endothelial dysfunction and obesity-associated cardiovascular diseases.

Topics: Animals; Cytokines; Endothelium, Vascular; Glucosides; GPI-Linked Proteins; Humans; Hypertension; Lectins; Male; Mice; Mice, Knockout; Rats; Rats, Zucker; Stilbenes

Despite knowing that resveratrol has effects on blood vessels, blood pressure and that phytostrogens can also improve the endothelium-dependent relaxation/vasodilation, there are no reports of reveratrol's direct effect on the endothelial function and blood pressure of animals with estrogen deficit (mimicking post-menopausal increased blood pressure).. To verify the effect of two different periods of preventive treatment with resveratrol on blood pressure and endothelial function in ovariectomized young adult rats.. 3-month old female Wistar rats were used and distributed in 6 groups: intact groups with 60 or 90 days, ovariectomized groups with 60 or 90 days, and ovariectomized treated with resveratrol (10 mg/kg of body weight per day) for 60 or 90 days. The number of days in each group corresponds to the duration of the experimental period. Vascular reactivity study was performed in abdominal aortic rings, systolic blood pressure was measured and serum nitric oxide (NO) concentration was quantified.. Ovariectomy induced blood pressure increase 60 and 90 days after surgery, whereas the endothelial function decreased only 90 days after surgery, with no difference in NO concentration among the groups. Only longer treatment (90 days) with resveratrol was able to improve the endothelial function and normalize blood pressure.. Our results suggest that 90 days of treatment with resveratrol is able to improve the endothelial function and decrease blood pressure in ovariectomized rats.. Apesar de se saber que o resveratrol apresenta efeitos sobre a pressão arterial e os vasos sanguíneos, e que os fitoestrógenos podem melhorar o relaxamento/vasodilatação dependente do endotélio, não há relatos do efeito direto do resveratrol sobre a pressão arterial e a função endotelial em animais com deficiência de estrógeno (mimetizando a pressão arterial aumentada pós-menopausa).. Verificar o efeito de dois diferentes períodos de tratamento preventivo com resveratrol sobre a pressão arterial e a função endotelial em ratas adultas jovens ovariectomizadas.. Foram utilizadas ratas Wistar com 3 meses de idade, distribuídas em 6 grupos: grupos intactas com 60 ou 90 dias, grupos ovariectomizadas com 60 ou 90 dias, grupos ovariectomizadas e tratadas com resveratrol na dose de 10mg/kg de massa corporal por dia, durante 60 ou 90 dias, sendo o número de dias em cada grupo relativo à duração do período experimental. Foi realizado um estudo de reatividade vascular em anéis da aorta abdominal, mensurada a pressão arterial sistólica e quantificada a concentração sérica de óxido nítrico (NO).. A ovariectomia induziu aumento da pressão arterial 60 e 90 dias após a cirurgia, enquanto a função endotelial decaiu apenas após 90 dias, e não houve diferença na concentração de NO entre os grupos. Apenas o tratamento prolongado com resveratrol (90 dias) foi capaz de melhorar a função endotelial e normalizar a pressão arterial.. Nossos resultados sugerem que o tratamento por 90 dias com resveratrol é capaz de melhorar a função endotelial e diminuir a pressão sanguínea em ratas ovariectomizadas.

Topics: Animals; Antioxidants; Blood Pressure; Endothelium, Vascular; Estrogens; Female; Hypertension; Nitrates; Nitric Oxide; Nitrites; Ovariectomy; Rats, Wistar; Reference Values; Reproducibility of Results; Resveratrol; Stilbenes; Time Factors; Treatment Outcome

Maternal high-fat (HF) diet is believed to induce oxidative stress and activate nutrient-sensing signals, which increase the risk of adult offspring to develop hypertension. We investigated whether resveratrol prevents the combined maternal plus postweaning HF-diets-induced hypertension in adult male offspring, with a focus on the kidney. Female Sprague-Dawley rats received either a normal diet (ND) or HF diet (D12331, Research Diets) for 5 weeks before mating and during gestation and lactation. The male offspring were placed on either the ND or HF diet from weaning to 4 months of age, resulting in four experimental groups (maternal diet/postweaning diet; n=8-10/group): ND/ND, ND/HF, HF/ND and HF/HF. Another group of HF/HF rats (n=10) was treated with 0.5% resveratrol in drinking water between 2 and 4 months of age (HF/HF+R). Rats were killed at 4 months of age. We found that HF/HF-induced hypertension in adult offspring was prevented by resveratrol. Resveratrol mediated its protective effect on HF/HF-induced hypertension in the kidneys of male offspring by diminishing oxidative stress; reducing renal asymmetric dimethylarginine levels; mediating the renin-angiotensin system (RAS) in favor of vasodilatation; restoring nutrient-sensing pathways via increased levels of silent information regulator transcript 1 (SIRT1), AMP-activated protein kinase 2α and peroxisome proliferator-activated receptor gamma coactivator 1-α; and inducing autophagy. Our data implicated an association between oxidative stress, RAS, nitric oxide, and nutrient-sensing signals in HF/HF-induced hypertension. Resveratrol, acting as an antioxidant as well as a SIRT1 activator, might be a therapeutic approach for hypertension.

Topics: Animals; Arginine; Blood Pressure; Diet, High-Fat; Female; Hypertension; Male; Maternal Nutritional Physiological Phenomena; Oxidative Stress; Pregnancy; Rats, Sprague-Dawley; Renin-Angiotensin System; Resveratrol; Stilbenes; Weaning

Obesity is a major risk for hypertension. Endothelial dysfunction contributes to increased peripheral vascular resistance and subsequent hypertension. Autophagy regulates endothelial function, however, whether autophagy is related to hypertension in obesity remains largely unclear. We wished to ascertain: (i) the role of autophagy in obesity-induced hypertension and the underlying mechanisms; (ii) if tetrahydroxystilbene glycoside (TSG) influences endothelial dysfunction and obesity-associated hypertension.. (TSG-treated) male Zucker diabetic fatty (ZDF) rats and cultured human umbilical vein endothelial cells (HUVECs) were used. Blood pressure was measured non-invasively with a tail-cuff system. Westernblotting was performed to determine the expression of autophagy-associated proteins. Autophagy flux was assessed by transfection HUVECs with the Ad-mGFP-RFP-LC3.. Compared with their lean counterparts, obese ZDF rats exhibited hypertension and endothelial dysfunction, along with impaired Akt/mTOR signaling and upregulated expression of autophagy-associated proteins beclin1, microtubule-associated protein 1 light chain 3 II/I, autophagy protein (ATG)5 and ATG7. Two-week TSG administration restored blood pressure and endothelial function, reactivated Akt/mTOR pathway and decreased endothelial autophagy in ZDF rats. Rapamycin pretreatment blocked the hypotensive effect of TSG in ZDF rats. Suppression of Akt/mTOR expression with siRNA significantly blunted the anti-autophagic effect of TSG in HUVECs as evidenced by abnormal autophagic flux and increased expression of autophagy-associated proteins.. Endothelial dysfunction in ZDF rats is partially attributable to excessive autophagy. TSG improves endothelial function and exerts hypotensive effects via regulation of endothelial autophagy.

Topics: Animals; Apoptosis; Autophagy; Blood Pressure; Glycosides; Human Umbilical Vein Endothelial Cells; Humans; Hypertension; Male; Microtubule-Associated Proteins; Obesity; Proto-Oncogene Proteins c-akt; Rats; Rats, Zucker; RNA Interference; Signal Transduction; Sirolimus; Stilbenes; TOR Serine-Threonine Kinases; Up-Regulation; Vasodilation

Topics: Animals; Blood Pressure; Disease Models, Animal; Hypertension; Male; Mesenteric Arteries; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Vascular Resistance

Exaggerated cyclooxygenase (COX) and thromboxane-prostanoid (TP) receptor-mediated endothelium-dependent contraction can contribute to endothelial dysfunction. This study examined the effect of resveratrol (RSV) on endothelium-dependent contraction and cell signaling in the common carotid artery (CCA) from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Acetylcholine (Ach)-stimulated endothelium-dependent nitric oxide synthase (NOS)-mediated relaxation in precontracted SHR CCA was impaired (maximum 73 ± 6% vs. 87 ± 5% in WKY) (P < 0.05) by competitive COX-mediated contraction. Chronic (28-day) treatment in vivo (drinking water) with a ∼0.075 mg·kg(-1)·day(-1) RSV dose affected neither endothelium-dependent relaxation nor endothelium-dependent contraction and associated prostaglandin (PG) production evaluated in non-precontracted NOS-blocked CCA. In contrast, a chronic ∼7.5 mg·kg(-1)·day(-1) RSV dose improved endothelium-dependent relaxation (94 ± 6%) and attenuated endothelium-dependent contraction (58 ± 4% vs. 73 ± 5% in No-RSV) and PG production (183 ± 43 vs. 519 ± 93 pg/ml) in SHR CCA, while U46619-stimulated TP receptor-mediated contraction was unaffected. In separate acute in vitro experiments, 20-μM RSV preincubation attenuated endothelium-dependent contraction (6 ± 4% vs. 62 ± 2% in No Drug) and PG production (121 ± 15 vs. 491 ± 93 pg/ml) and attenuated U46619-stimulated contraction (134 ± 5% vs. 171 ± 4%) in non-precontracted NOS-blocked SHR CCA. Compound C, a known AMP-activated protein kinase (AMPK) inhibitor, did not prevent the RSV attenuating effect on Ach- and U46619-stimulated contraction but did prevent the RSV attenuating effect on PG production (414 ± 58 pg/ml). These data demonstrate that RSV can attenuate endothelium-dependent contraction both by suppressing arterial wall PG production, which may be partially mediated by AMPK, and by TP receptor hyporesponsiveness, which does not appear to be mediated by AMPK.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; AMP-Activated Protein Kinases; Animals; Carotid Artery, Common; Endothelium, Vascular; Hypertension; Male; Muscle Contraction; Nitric Oxide Synthase Type III; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Thromboxane; Resveratrol; Signal Transduction; Stilbenes; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

This study was undertaken to determine whether perinatal maternal resveratrol (Resv)--a phytoalexin known to confer cardiovascular protection--could prevent the development of hypertension and improve vascular function in adult spontaneously hypertensive rat offspring. Dams were fed either a control or Resv-supplemented diet (4 g/kg diet) from gestational day 0.5 until postnatal day 21. Indwelling catheters were used to assess blood pressure and vascular function in vivo; wire myography was used to assess vascular reactivity ex vivo. Perinatal Resv supplementation in dams had no effect on fetal body weights, albeit continued maternal treatment postnatally resulted in growth restriction in offspring by postnatal day 21; growth restriction was no longer evident after 5 weeks of age. Maternal perinatal Resv supplementation prevented the onset of hypertension in adult offspring (-18 mm Hg; P=0.007), and nitric oxide synthase inhibition (with L-NG-nitroarginine methyl ester) normalized these blood pressure differences, suggesting improved nitric oxide bioavailability underlies the hemodynamic alterations in the Resv-treated offspring. In vivo and ex vivo, vascular responses to methylcholine were not different between treatment groups, but prior treatment with L-NG-nitroarginine methyl ester attenuated the vasodilation in untreated, but not Resv-treated adult offspring, suggesting a shift toward nitric oxide-independent vascular control mechanisms in the treated group. Finally, bioconversion of the inactive precursor big endothelin-1 to active endothelin-1 in isolated mesenteric arteries was reduced in Resv-treated offspring (-28%; P<0.05), and this difference could be normalized by L-NG-nitroarginine methyl ester treatment. In conclusion, perinatal maternal Resv supplementation mitigated the development of hypertension and causes persistent alterations in vascular responsiveness in spontaneously hypertensive rats.

Topics: Adult; Adult Children; Animals; Animals, Newborn; Dietary Supplements; Disease Models, Animal; Female; Humans; Hypertension; Male; Perinatal Care; Pregnancy; Pregnancy, Animal; Random Allocation; Rats; Rats, Inbred SHR; Reference Values; Resveratrol; Stilbenes

Resveratrol, a polyphenol of natural compounds, has beneficial cardiovascular effects, many of which are mediated by nitric oxide (NO). Resveratrol increases intracellular calcium and activates AMP-activated protein kinase (AMPK), all of which could increase NO production. We hypothesized that resveratrol via a calcium-dependent NO production lowers blood pressure (BP) in spontaneously hypertensive rats (SHR).. Acetylcholine (Ach)-induced endothelium-dependent relaxations in rat aortas were examined by organ chamber. Blood pressures were determined by radiotelemetry methods.. Incubation of isolated aortas from SHR with resveratrol dramatically improved vasorelaxation induced by Ach. Preincubation of aortas with endothelial NO synthase (eNOS) inhibitor or calcium chelant blunted the effects of resveratrol on Ach-induced relaxation, as wells as NO production and eNOS phosphorylation. In animal studies, administration of resveratrol significantly lowered systemic BP in SHR.. Resveratrol increases endothelial NO production to improve endothelial dysfunction and lowers BP in hypertensive rats, which depends on calcium-eNOS activation.

Topics: Acetylcholine; Animals; Antioxidants; Aorta; Blood Pressure; Calcium; Disease Models, Animal; Hypertension; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Rats; Rats, Inbred SHR; Resveratrol; Stilbenes; Vasodilation

Micro-inflammation plays an important role in the pathogenesis of spontaneously hypertensive rat (SHR). In the present study, we investigated the therapeutic potential of resveratrol (RSV), a polyphenol with anti-fibrosis activity in hypertensive renal damage model. In SHR renal damage model, RSV treatment blunted the increase in urine albumin excretion, urinary β2-microglobulin (β2-MG), attenuated the decrease in creatinine clearance rate (CCR). The glomerular sclerosis index (1.54±0.33 compared with 0.36±0.07) and tubulointerstitial fibrosis (1.57±0.31 compared with 0.19±0.04) were significantly higher in SHRs compared with Wistar Kyoto rats (WKYs), which were significantly lower by RSV treatment. The increases in mesangium accumulation and the expression of renal collagen type I (Col I), fibronectin (Fn), plasminogen activator inhibitor-1 (PAI-1) and transforming growth factor-β1 (TGF-β1) in SHR were also reduced by RSV treatment. Nuclear factor κB (NF-κB) expression was increased in the cytoplasm and nuclei of the SHR kidneys, which was significantly decreased by RSV treatment. Furthermore, the protein level of IκB-α significantly decreased in the kidneys of the SHR when compared with the WKYs. RSV treatment partially restored the decreased IκB-α level. In SHR kidney, increased expression of interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein 1 (MCP-1) were observed. These changes were attenuated by RSV treatment. No changes in blood pressure were detected between SHR group and SHR + RSV group. Taken together, the present study demonstrated that RSV treatment may significantly attenuate renal damage in the SHR model of chronic kidney disease (CKD). The renal protective effect is associated with inhibition of IL-6, ICAM-1 and MCP-1 expression via the regulation of the nuclear translocation of NF-κB, which suggesting that micro-inflammation may be a potential therapeutic target of hypertensive renal damage.

Topics: Acute Kidney Injury; Animals; beta 2-Microglobulin; Blood Pressure; Collagen Type I; Disease Models, Animal; Fibronectins; Fibrosis; Gene Expression Regulation; Humans; Hypertension; Inflammation; Kidney; Plasminogen Activator Inhibitor 1; Rats; Resveratrol; Stilbenes; Transforming Growth Factor beta1

Recent studies have reported that the activation of AMP-activated protein kinase (AMPK) suppressed oxidative stress. The aim of this study was to examine whether the activation of AMPK in the brain decreased Rac1-induced ROS generation, thereby reducing blood pressure (BP) in rats with fructose-induced hypertension. The inhibition of ROS by treatment with an AMPK activator (oral resveratrol, 10 mg/kg/day) for 1 week decreased the BP and increased the NO production in the rostral ventrolateral medulla (RVLM) of fructose-fed rats but not in control Wistar-Kyoto (WKY) rats. In addition, resveratrol treatment abolished the Rac1-induced increases in the activity of the NADPH oxidase subunits p22-phox and reduced the activity of SOD2, while treatment with an AMPK inhibitor (compound C, 40 μM/day) had the opposite effect, in the fructose-fed rats. Interestingly, the activation of AMPK abolished Rac1 activation and decreased BP by inducing the activities of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and ribosomal protein S6 kinase (RSK) and nNOS phosphorylation in the fructose-fed rats. We conclude that the activation of AMPK decreased BP, abolished ROS generation, and enhanced ERK1/2-RSK-nNOS pathway activity by negatively regulating Racl-induced NADPH oxidase levels in the RVLM during oxidative stress-associated hypertension.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Blood Pressure; Disease Models, Animal; Enzyme Activators; Fructose; Hypertension; rac1 GTP-Binding Protein; Rats, Inbred WKY; Reactive Oxygen Species; Resveratrol; Stilbenes

This study investigated possible mechanisms for cardioprotective effects of lipoic acid (LA), quercetin (Q) and resveratrol (R) on oxidative stress related to thyroid hormone alterations in long-term obesity. Female C57BL/6 mice were fed on high-fat diet (HFD), HFD+LA, HFD+R, HFD+Q and normal diet for 26weeks. Body weight, blood pressure, thyroid hormones, oxidative stress markers, angiotensin converting enzyme (ACE), nitric oxide synthase (NOS) and ion pump activities were measured, and expression of cardiac genes was analyzed by real-time polymerase chain reaction. HFD induced marked increase (P<.05) in body weight, blood pressure and oxidative stress, while plasma triidothyronine levels reduced. ACE activity increased (P<.05) in HFD mice (0.69±0.225U/mg protein) compared with controls (0.28±0.114U/mg protein), HFD+LA (0.231±0.02U/mg protein) and HFD+Q (0.182±0.096U/mg protein) at 26weeks. Moreover, Na(+)/K(+)-ATPase and Ca(2+)-ATPase activities increased in HFD mice whereas NOS reduced. A 1.5-fold increase in TRα1 and reduction in expression of the deiodinase iodothyronine DIO1, threonine protein kinase and NOS3 as well as up-regulation of AT1α, ACE, ATP1B1, GSK3β and Cja1 genes also occurred in HFD mice. Conversely, LA, Q and R inhibited weight gain; reduced TRα1 expression as well as increased DIO1; reduced ACE activity and AT1α, ATP1B1 and Cja1 gene expression as well as inhibited GSK3β; increased total antioxidant capacity, GSH and catalase activity; and reduced blood pressure. In conclusion, LA, resveratrol and quercetin supplementation reduces obesity thereby restoring plasma thyroid hormone levels and attenuating oxidative stress in the heart and thus may have therapeutic potential in heart diseases.

Topics: Animals; Anti-Obesity Agents; Antihypertensive Agents; Antioxidants; Biomarkers; Cardiotonic Agents; Cardiovascular Diseases; Diet, High-Fat; Female; Gene Expression Regulation; Heart Ventricles; Hypertension; Hypothyroidism; Mice, Inbred C57BL; Obesity; Oxidative Stress; Quercetin; Random Allocation; Resveratrol; Stilbenes; Thioctic Acid; Thyroid Hormones; Weight Gain

Autophagy exists in vascular endothelial cells, but the relationship between autophagy and blood vessel dysfunction in hypertension remains elusive. This study aimed to investigate role of autophagy in vascular endothelial dysfunction in prehypertension and hypertension and the underlying mechanisms involved. Furthermore, we sought to determine if and how tetrahydroxystilbene glucoside (TSG), a resveratrol analogue and active ingredient of Polygonum multiflorum Thunb used for its cardiovascular protective properties in traditional Chinese medicine, influences vascular endothelial function. Male spontaneously hypertensive rats (SHRs) aged 4 weeks (young) and 12 weeks (adult) were studied and the vascular function of isolated aorta and mesenteric artery was assessed in vitro. Compared with Wistar Kyoto rats (WKY), young and adult SHRs showed endothelial dysfunction of the aorta and mesenteric artery, along with decreased pAkt, pmTOR, and autophagic marker protein p62 and increased LC3 II/I in microvascular but not aortic tissues. TSG administration for 14 days significantly improved mesenteric vascular endothelial function, increased levels of pAkt and pmTOR, and decreased autophagy. Pretreatment of young SHRs with the mTOR inhibitor rapamycin blocked the antiautophagic and vasodilative effects of TSG. Moreover, TSG significantly activated Akt-mTOR signaling in HUVECs and reduced the autophagic levels in vitro, which were almost completely blocked by rapamycin. In summary, mesenteric endothelial dysfunction in prehypertensive SHRs was at least partly attributable to excessive autophagy in vascular tissues. TSG partly restored microvascular endothelial dysfunction through activating the Akt/mTOR pathway, which consequently suppressed autophagy, indicating that TSG could be potentially applied to protect vascular function against subclinical changes in prehypertension.

Topics: Animals; Autophagy; Depression, Chemical; Endothelial Cells; Endothelium, Vascular; Fallopia multiflora; Glucosides; Humans; Hypertension; In Vitro Techniques; Male; Microvessels; Phytotherapy; Proto-Oncogene Proteins c-akt; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; Stilbenes; TOR Serine-Threonine Kinases; Vasodilator Agents

Hypertension is a risk factor for the cardiovascular diseases. Although, several drugs are used to treat hypertension, the success of the antihypertensive therapy is limited. Resveratrol decreases blood pressure in animal models of hypertension. This study researched the mechanisms behind the effects of resveratrol on hypertension. Hypertension was induced by using the deoxycorticosterone acetate (DOCA)-induced (15 mg/kg twice per week, subcutaneously) salt-sensitive hypertension model of Wistar rats. Hypertension caused a decrease in endothelium-dependent relaxations of the isolated thoracic aorta. Resveratrol treatment (50 mg/l in drinking water) prevented DOCA salt-induced hypertension, but did not improve endothelial dysfunction. Plasma nitric oxide (NO), asymmetric dimethylarginine (ADMA), total antioxidant capacity (TAC) and hydrogen sulfide (H2S) levels were not changed by DOCA salt application. However, treatment of resveratrol significantly decreased ADMA and increased TAC and H2S levels. NO level in circulation was not significantly changed by resveratrol. DOCA salt application and resveratrol treatment also caused an alteration in the epigenetic modification of vessels. Staining pattern of histone 3 lysine 27 methylation (H3K27me3) in the aorta and renal artery sections was changed. These results show that preventive effect of resveratrol on DOCA salt-induced hypertension might due to its action on the production of some blood biomarkers and the epigenetic modification of vessels that would focus upon new aspect of hypertension prevention and treatment.

Topics: Animals; Antioxidants; Arginine; Biomarkers; Blood Pressure; Blood Vessels; Desoxycorticosterone Acetate; Endothelium, Vascular; Fluorescent Antibody Technique; Histones; Hydrogen Sulfide; Hypertension; Lysine; Male; Methylation; Nitrites; Rats, Wistar; Renal Artery; Resveratrol; Stilbenes; Systole; Vasodilation

Recent studies demonstrate that aging exacerbates hypertension-induced cognitive decline, but the specific age-related mechanisms remain elusive. Cerebral microhemorrhages (CMHs) are associated with rupture of small intracerebral vessels and are thought to progressively impair neuronal function. To determine whether aging exacerbates hypertension-induced CMHs young (3 months) and aged (24 months) mice were treated with angiotensin II plus L-NAME. We found that the same level of hypertension leads to significantly earlier onset and increased incidence of CMHs in aged mice than in young mice, as shown by neurological examination, gait analysis, and histological assessment of CMHs in serial brain sections. Hypertension-induced cerebrovascular oxidative stress and redox-sensitive activation of matrix metalloproteinases (MMPs) were increased in aging. Treatment of aged mice with resveratrol significantly attenuated hypertension-induced oxidative stress, inhibited vascular MMP activation, significantly delayed the onset, and reduced the incidence of CMHs. Collectively, aging promotes CMHs in mice likely by exacerbating hypertension-induced oxidative stress and MMP activation. Therapeutic strategies that reduce microvascular oxidative stress and MMP activation may be useful for the prevention of CMHs, protecting neurocognitive function in high-risk elderly patients.

Topics: Aging; Animals; Blood Pressure; Brain; Disease Models, Animal; Hypertension; Intracranial Hemorrhages; Male; Mice, Inbred C57BL; Oxidation-Reduction; Oxidative Stress; Resveratrol; Stilbenes

Compelling evidence supports the role of oxidative stress and renal interstitial inflammation in the pathogenesis of hypertension. Resveratrol is a polyphenolic stilbene, which can lower oxidative stress by activating the transcription factor nuclear factor-E2-related factor-2 (Nrf2), the master regulator of numerous genes encoding antioxidant and phase II-detoxifying enzymes and molecules. Given the role of oxidative stress and inflammation in the pathogenesis of hypertension, we conducted this study to test the hypothesis that long-term administration of resveratrol will attenuate renal inflammation and oxidative stress and, hence, progression of hypertension in the young spontaneously hypertensive rats (SHR). SHR and control [Wistar-Kyoto (WKY)] rats were treated for 9 wk with resveratrol or vehicle in their drinking water. Vehicle-treated SHR exhibited renal inflammatory injury and oxidative stress, as evidenced by glomerulosclerosis, tubulointerstitial injury, infiltration of inflammatory cells, and increased levels of renal 8-isoprostane and protein carbonylation. This was associated with reduced antioxidant capacity and downregulations of Nrf2 and phase II antioxidant enzyme glutathione-S-transferase (GST). Resveratrol treatment mitigated renal inflammation and injury, reduced oxidative stress, normalized antioxidant capacity, restored Nrf2 and GST activity, and attenuated the progression of hypertension in SHR. However, resveratrol had no effect on these parameters in WKY rats. In conclusion, development and progression of hypertension in the SHR are associated with inflammation, oxidative stress, and impaired Nrf2-GST activity in the kidney. Long-term administration of resveratrol restores Nrf2 expression, ameliorates inflammation, and attenuates development of hypertension in SHR. Clinical studies are needed to explore efficacy of resveratrol in human hypertension.

Topics: Animals; Antioxidants; Blood Pressure; Body Weight; Drinking; Eating; Hypertension; Inflammation; Kidney; Male; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Resveratrol; Stilbenes

Combretastatin A-4 phosphate (CA4P), a tubulin depolymerizing agent, shows promise in anti-cancer therapy and is associated with dose-dependent transient hypertension. The cardiac consequence of this hypertensive effect is unknown. This study was conducted to examine the cardiotoxic effect of CA4P on a rat model of hypertension. Hypertensive rats were created by feeding a 6% high salt (HS) diet to Dahl salt sensitive (DSS) rats for 2.5weeks. Cardiac toxicity was measured using serum troponin I levels 24h after CA4P administration. In rats fed HS diet, there was a significant increase in mean arterial blood pressure (MAP) from baseline, which was further increased by 80% following CA4P administration with peak systolic blood pressure (BP) of 247mmHg. Treatment with the calcium channel blockers, diltiazem and nicardipine, completely inhibited the hypertensive effects of CA4P. Nitroglycerin or enalapril, however, failed to completely block the hypertensive effects of CA4P. CA4P injection also significantly increased the cardiac troponin I level in hypertensive rats though pretreatment with diltiazem effectively blocked troponin I increase after CA4P administration. Based on these findings, an exaggerated hypertensive response to CA4P is associated with myocardial damage in hypertensive rats. Calcium channel blockers effectively blocked both CA4P induced hypertension and cardiac damage.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Diltiazem; Female; Hypertension; Phosphates; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; Stilbenes

Resveratrol, a phytoalexin, is reported to activate AMP-activated protein kinase (AMPK) in vascular cells. Activation of AMPK induces vasorelaxation to lower blood pressure (BP). Whether resveratrol via activation of AMPK decreases, BP remains unknown.. Male wild-type (WT) mice and mice deficient in AMPKα2 (AMPKα2(-/-)) were fed with resveratrol (400 mg/kg). After 7 d, mice were implanted with deoxycorticosterone acetate (DOCA)-salt (150 mg/kg) for 35 d. BP was detected by the radiotelemetry method. Vessel contraction was determined by organ chamber. Active RhoA, Rho-associated kinase (ROCK) activity, phosphorylations of myosin light chain (MLC), and myosin phosphatase targeting subunit 1 (MYPT1) were assayed by western blot.. Implantation of DOCA-salt dramatically increased systemic BPs (systolic BP and diastolic BP) in WT and AMPKα2(-/-) mice. However, treatment of resveratrol significantly decreased systemic BP in WT mice but not in AMPKα2(-/-) mice. In the organ chamber study, resveratrol inhibited agonist-induced vessel relaxation in WT mice aortas. Loss of AMPKα2 or AMPK inhibition by compound C reversed resveratrol-suppressed vasoconstriction in isolated mice aortas. In cultured vascular smooth muscle cells (VSMCs), activation of AMPK by resveratrol inhibited phenylephrine-enhanced MLC phosphorylation in a dose-dependent manner.. Resveratrol via activation of AMPK lowers BP in DOCA-hypertensive mice through an AMPK/RhoA/ROCK2/MLCMLC pathway.

Topics: AMP-Activated Protein Kinases; Animals; Anticarcinogenic Agents; Blood Pressure; Desoxycorticosterone Acetate; Disease Models, Animal; Enzyme Activation; Hypertension; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Resveratrol; Stilbenes; Vasoconstriction; Vasodilator Agents

Pressure overload has an important role in heart failure, inducing excessive autophagy in cardiac myocytes that is considered to be pathogenic. Resveratrol has been reported to improve cardiac dysfunction induced by pressure overload, but it has been unclear whether resveratrol ameliorates cardiac dysfunction by regulating autophagy. In this study, heart failure was induced in rats by constriction of the abdominal aorta. Four weeks after surgery, the rats with heart failure were randomized to treatment with resveratrol (8 mg · kg(-1) · d(-1) by intraperitoneal injection) for 28 days or to intraperitoneal injection of the vehicle (propylene glycol) alone. Echocardiography was performed to assess cardiac function. Expression of brain natriuretic peptide messenger RNA in the left ventricle was detected by real-time polymerase chain reaction, whereas expression of proteins associated with autophagy (beclin-1 and lamp-1) was detected by western blotting and immunohistochemistry. Furthermore, autophagic vacuoles were detected in the heart by transmission electron microscopy, and the myocardial ATP content was measured by the bioluminescence method. Treatment with resveratrol significantly improved cardiac dysfunction and reduced brain natriuretic peptide expression in rats with heart failure. Resveratrol down-regulated beclin-1 and lamp-1 expression and also inhibited the formation of autophagic vacuoles in failing hearts. Furthermore, resveratrol restored the myocardial ATP level and reduced phosphorylation of AMP-activated protein kinase at Thr172. These results suggest that resveratrol may inhibit autophagy through inactivation of AMP-activated protein kinase and restoration of ATP in heart failure induced by pressure overload. Accordingly, resveratrol may be beneficial for patients with hypertensive heart disease.

Topics: Adenosine Triphosphate; AMP-Activated Protein Kinases; Animals; Autophagy; Blotting, Western; Cardiotonic Agents; Disease Models, Animal; Heart Failure; Heart Function Tests; Hypertension; Male; Myocardium; Rats, Sprague-Dawley; Resveratrol; Stilbenes

We investigated the contribution of cytochrome P450 (CYP) 1B1 to hypertension and its pathogenesis by examining the effect of its selective inhibitor, 2,4,3',5'-tetramethoxystilbene (TMS), in spontaneously hypertensive rats (SHR).. Blood pressure (BP) was measured bi-weekly. Starting at 8 weeks, TMS (600 μg/kg, i.p.) or its vehicle was injected daily. At 14 weeks, samples were collected for measurement.. TMS reversed increased BP in SHR (207 ± 7 vs. 129 ± 2 mmHg) without altering BP in Wistar-Kyoto rats. Increased CYP1B1 activity in SHR was inhibited by TMS (RLU: aorta, 5.4 ± 0.7 vs. 3.7 ± 0.7; heart, 6.0 ± 0.8 vs. 3.4 ± 0.4; kidney, 411 ± 45 vs. 246 ± 10). Increased vascular reactivity, cardiovascular hypertrophy, endothelial and renal dysfunction, cardiac and renal fibrosis in SHR were minimized by TMS. Increased production of reactive oxygen species and NADPH oxidase activity in SHR, were diminished by TMS. In SHR, TMS reduced increased plasma levels of nitrite/nitrate (46.4 ± 5.0 vs. 28.1 ± 4.1 μM), hydrogen-peroxide (36.0 ± 3.7 vs. 14.1 ± 3.8 μM), and thiobarbituric acid reactive substances (6.9 ± 1.0 vs. 3.4 ± 1.5 μM). Increased plasma levels of pro-inflammatory cytokines and catecholamines, and cardiac activity of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, c-Src tyrosine kinase, and protein kinase B in SHR were also inhibited by TMS.. These data suggests that increased oxidative stress generated by CYP1B1 contributes to hypertension, increased cytokine production and sympathetic activity, and associated pathophysiological changes in SHR. CYP1B1 could be a novel target for developing drugs to treat hypertension and its pathogenesis.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Blood Pressure; Cardiovascular System; Catecholamines; Cytochrome P-450 CYP1B1; Cytokines; Endothelium, Vascular; Fibrosis; Genes, src; Hydrogen Peroxide; Hypertension; Hypertrophy; Kidney; Kidney Diseases; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Muscle, Smooth; NADPH Oxidases; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reactive Oxygen Species; Stilbenes; Superoxides; Thiobarbituric Acid Reactive Substances

Oxidative stress is an important pathogenic factor in the development of hypertension. Resveratrol, the main antioxidant in red wine, improves NO bioavailability and prevents cardiovascular disease. The aim of this study was to examine whether resveratrol decreases the generation of reactive oxygen species (ROS), thereby reducing BP in rats with fructose-induced hypertension.. Rats were fed 10% fructose with or without resveratrol (10 mg·kg(-1) ·day(-1) ) for 1 week or for 4 weeks with resveratrol treatment beginning at week 2; systolic BP (SBP) was measured by tail-cuff method. Endogenous in vivo O2 (-) production in the nucleus tractus solitarii (NTS) was determined with dihydroethidium. Real-time PCR and immunoblotting analyses were used to quantify RNA and protein expression levels.. In fructose-fed rats, ROS levels in the NTS were higher, whereas the NO level was significantly decreased. Also, RNA and protein levels of NADPH oxidase subunits (p67, p22-phox) were elevated, superoxide dismutase 2 (SOD2) reduced and AMP-activated PK (AMPK) T172 phosphorylation levels in the NTS were lower in fructose-fed rats. Treatment with the AMPK activator resveratrol decreased levels of NADPH oxidase subunits and ROS, and increased NO and SOD2 levels in the NTS of fructose-fed rats. Administration of resveratrol, in combination with fructose at week 0 and later at week 2, significantly reduced the SBP of fructose-fed rats.. Collectively, resveratrol decreased BP through the phosphorylation of AMPK, Akt and neuronal NOS in fructose-fed rats. These novel findings suggest that resveratrol may be a potential pharmacological candidate for the treatment of hypertension.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Blood Pressure; Cerebellum; Fructose; Hypertension; Male; NADPH Oxidases; Nitric Oxide Synthase Type I; Nitrogen Oxides; Oxidative Stress; Proto-Oncogene Proteins c-akt; Rats, Inbred WKY; Reactive Oxygen Species; Resveratrol; Solitary Nucleus; Stilbenes; Superoxide Dismutase; Superoxide Dismutase-1

The purpose of this study was to determine the effects of resveratrol (RSV) and the molecular mechanisms by which it regulates vascular smooth muscle contraction and blood pressure in mice. In cultured human vascular smooth muscle cells (VSMCs), we found that the activation of AMP-activated protein kinase (AMPK) by RSV inhibited angiotensin II (AngII)-induced phosphorylation of myosin phosphatase-targeting subunit 1 (MYPT1) and myosin light chain (MLC). Inversely, AMPK inhibition with RNA interference and compound C, an AMPK inhibitor, abolished the inhibitory effect of RSV on AngII-induced MYPT1 and MLC phosphorylation. Thiazovivin, a Rho-associated kinase (ROCK) inhibitor, reversed AngII-induced MYPT1 and MLC phosphorylation, suggesting that ROCK functions as an upstream kinase for MYPT1/MLC. RSV reversed AngII-induced Ras homolog gene family member A (RhoA) and ROCK activity, whereas AMPK inhibition via pharmacological or genetic means abolished this effect. In addition, gene silencing of p190-guanosine triphosphatase-activating protein blocked the effects of RSV-induced AMPK activation on MLC, MYPT1 and RhoA in VSMCs. Ex vivo analyses demonstrated that AngII-induced aorta contractions were dramatically inhibited by RSV, and this effect was abolished by AMPK inhibition. Finally, daily chronic administration of RSVl alleviated hypertension in the experimental model of AngII-induced hypertensive mice, and these effects were accompanied by the activation of AMPK, significantly decreased RhoA activity and phosphorylation levels of MYPT1 and MLC in AngII-treated murine aortic VSMCs. More importantly, administration of compound C significantly abolished the effects of RSV. In conclusion, AMPK suppression of the p190-GAP-dependent RhoA/ROCK/MYPT1/MLC pathway contributes to the hypotensive effect of RSV in AngII-treated mice.

Topics: Adenylate Kinase; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Hypertension; Mice; Muscle Contraction; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Resveratrol; rho-Associated Kinases; rhoA GTP-Binding Protein; Stilbenes

Resveratrol (RESV) is a polyphenol with pleiotropic effects that include reduction of oxidative stress and increased vascular nitric oxide (NO) production. However, whether or not RESV can prevent rises in blood pressure (BP) is controversial and remains to be firmly established. The purpose of this study was to determine whether RESV attenuates elevated BP and subsequent adaptive cardiac hypertrophy and to better understand the mechanisms involved. The spontaneously hypertensive rat (SHR) and the angiotensin (Ang)-II infused mouse were used as hypertensive models. Compared to a standard control diet, consumption of diets containing RESV by SHRs and Ang-II hypertensive mice, markedly prevented rises in systolic BP. In addition, flow-mediated vasodilation was significantly improved by RESV in SHRs. RESV also reduced serum and cardiac levels of the lipid peroxidation by-product, 4-hydroxy-2-nonenal in the hypertensive rodents and inhibited the production of superoxide in human-derived endothelial cells. Analysis of mesenteric arteries from SHRs and Ang-II infused mice demonstrated that RESV increased endothelial NO synthase (eNOS) phosphorylation by enhancing the LKB1/adenosine monophosphate (AMP)-activated protein kinase (AMPK) signal transduction pathway. Moreover, RESV reduced hypertrophic growth of the myocardium through reduced hemodynamic load and inhibition of the p70 S6 kinase pro-hypertrophic signaling cascade. Overall, we show that high dose RESV reduces oxidative stress, improves vascular function, attenuates high BP and prevents cardiac hypertrophy through the preservation of the LKB1-AMPK-eNOS signaling axis.

Topics: Animals; Blood Pressure; Cardiomegaly; Cells, Cultured; Humans; Hypertension; Mice; Rats; Resveratrol; Stilbenes

Epidemiological studies have demonstrated that the Mediterranean diet, which is rich in resveratrol, is associated with a significantly reduced risk of cardiovascular disease. However, the molecular mechanisms that underlie the beneficial effects of resveratrol on cardiovascular function remain incompletely understood. Therefore, we set out to identify the molecular target(s) mediating the protective action of resveratrol on vascular function. To this end, we performed vascular reactivity studies to evaluate the effects of resveratrol on superior thyroid artery obtained from 59 patients with hypertension and dyslipidemia. We found that resveratrol evoked vasorelaxation and reduced endothelial dysfunction through the modulation of NO metabolism via (1) an 5' adenosine monophosphate-activated protein kinase-mediated increase in endothelial NO synthase activity; (2) a rise in tetrahydrobiopterin levels, which also increases endothelial NO synthase activity; and (3) attenuation of vascular oxidative stress, brought about by overexpression of manganese superoxide dismutase via an nuclear factor erythroid-derived 2-like 2-dependent mechanism. The effects of resveratrol on acetylcholine vasorelaxation were also tested in vessels from patients with nonhypertensive nondyslipidemia undergoing thyroid surgery. In this setting, resveratrol failed to exert any effect. Thus, our finding that resveratrol reduces endothelial dysfunction, an early pathophysiological feature and independent predictor of poor prognosis in most forms of cardiovascular disease, supports the concept that the risk of vascular events could be further reduced by adherence to a set of dietary and behavioral guidelines.

Topics: Acetylcholine; Biopterins; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; NF-E2-Related Factor 2; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphorylation; Resveratrol; Stilbenes; Superoxide Dismutase; Vasodilation

Cardiac hypertrophy and associated myocardial remodeling is one of the main complications of hypertension resulting in the development of heart failure. It is of great significance to explore novel treatments to reverse cardiac hypertrophy in hypertensives with or without affecting blood pressure. In the present study, we investigated whether low-dose resveratrol alone or in a combination with a blood pressure-lowering agent can reverse hypertension-induced cardiovascular dysfunction. Twenty-week-old male spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats were treated with resveratrol (2.5 mg kg⁻¹ per day) and/or hydralazine (25 mg kg⁻¹ per day) for 8 weeks. Blood pressure, cardiac structure and function, and electrocardiogram measurements were examined. Pressure myography of resistance arteries, histological examinations of heart tissues, oxidative stress and inflammatory measurements were also preformed to assess the efficacy of the treatment. Although resveratrol treatment alone was ineffective in reducing systolic blood pressure, diastolic blood pressure, diastolic dysfunction and vascular remodeling, it significantly prevented the systolic impairment and reduced myocardial fibrosis, and reduced oxidative stress and inflammation in hypertensive rats. Furthermore, a combination of resveratrol with hydralazine treatment significantly reduced blood pressure, improved systolic and diastolic function, decreased fibrosis and improved vascular geometry. In summary, low-dose resveratrol itself was unable to reduce systolic blood pressure, diastolic blood pressure, diastolic dysfunction and vascular remodeling. However, resveratrol alone alleviated cardiac fibrosis and some of the functional abnormalities in SHRs. And a combination of resveratrol with hydralazine was more effective than resveratrol or hydralazine alone in improving overall cardiovascular parameters.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cardiomegaly; Cardiovascular System; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hemodynamics; Hydralazine; Hypertension; Male; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Resveratrol; Stilbenes

Polyphenols consumption detected in red wine and grape juice may prevent or help in the treatment of hypertension. However, cardiovascular autonomic effects of polyphenols were poorly studied. Therefore, we evaluated the effects of resveratrol and grape juice treatments in hemodynamics, baroreflex sensitivity, heart rate (HR) and blood pressure (BP) variability and cardiac redox parameters. Male Wistar rats were divided in 3 groups (n=7/each) and treated for 30 days: only L-NAME-treated (60 mg/kg/day by oral gavage), L-NAME+resveratrol (L-NAME+R) and L-NAME+grape juice (L-NAME+G). BP signal was directly recorded and pulse interval (PI) and systolic arterial pressure (SAP) variability were analyzed in time and frequency domains. Baroreflex sensitivity (BRS) was determined by the alpha index. Oxidized and reduced glutathione concentrations were determined in cardiac tissue. L-NAME increased BP with no differences among groups (mean BP: L-NAME=124±4, L-NAME+R=126±3 and L-NAME+G=125±4 mmHg). PI and SAP variability expressed by total variance were also similar among groups. However, normalized low frequency (LF) and high frequency (HF) components of PI variability were lower and higher, respectively, in both R and G-treated groups when compared to only L-NAME group. Interestingly, sympathetic modulation to the vessels (LF from SAP variability) and BRS were decreased and increased, respectively, only in L-NAME+R rats. Additionally, GSH/GSSG ratios were higher in L-NAME+R and L-NAME+G than in L-NAME group. Our results indicate that resveratrol and grape juice treatments can modulate autonomic function and promote cardiac redox benefits even when nitric oxide is decreased. Moreover, resveratrol influences not only cardiac but also vascular autonomic modulation.

Topics: Animals; Autonomic Nervous System; Beverages; Cardiovascular System; Disease Models, Animal; Enzyme Inhibitors; Hemodynamics; Hypertension; Male; NG-Nitroarginine Methyl Ester; Oxidation-Reduction; Rats; Rats, Wistar; Resveratrol; Stilbenes; Vasodilator Agents; Vitis

As wine polyphenols were shown to possess many positive effects in mammals, including improvement of vascular function, this study investigated the effect of the Slovak Alibernet red wine extract (AWE) on blood pressure and vascular function in young normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Six weeks old, male, WKY and SHR were treated with AWE for three weeks at the dose of 24.2 mg/kg/day. Blood pressure (BP), determined by tail-cuff plethysmography, was significantly elevated in SHR vs. WKY and AWE failed to affect it. Lipid peroxidation was evaluated by determination of thiobarbituric acid-reactive substances. Vascular function was assessed in rings of the femoral artery using Mulvany-Halpern's myograph. Maximal endothelium-dependent acetylcholine (ACh)-induced relaxation was reduced in control SHR vs. WKY rats by approximately 9.3 %, which was associated with a significant decrease of its NO-independent component. AWE failed to affect maximal ACh-induced relaxation, both its NO-dependent and independent components, compared to controls of the same genotype. AWE however reduced lipid peroxidation in the left ventricle of both WKY and SHR and in the liver of SHR. In conclusion, three-week administration of AWE failed to reduce BP and to improve endothelial function in the femoral arteries of both genotypes investigated.

Topics: Animals; Blood Pressure; Dose-Response Relationship, Drug; Endothelium, Vascular; Hypertension; Male; Peripheral Arterial Disease; Plant Extracts; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Resveratrol; Stilbenes; Treatment Failure; Treatment Outcome; Vascular Resistance; Wine

We hypothesized that resveratrol, a natural phytoalexin found in grapes, can prevent oxidative stress, obesity and its related disturbances in obese rats programmed by early weaning. Lactating Wistar rats were separated into two groups: early weaning (EW) - dams who were wrapped with a bandage to interrupt the lactation in the last 3 days of lactation; control - dams whose pups had free access to milk during all lactation. At the 150th day, EW offspring were randomly subdivided into EW+resveratrol (EW+Res) - resveratrol (30 mg/kg/day); EW+vehicle (EW) - rats that received 0.5% (w/v) aqueous methylcellulose. The control group received vehicle. Rats were treated by gavage daily for 30 days. EW offspring developed hyperphagia, higher body weight, visceral obesity, higher systolic (SBP) and diastolic blood pressure (DBP) (+15% and +20%, respectively; P<.05) and higher serum triglycerides (TG) and low-density lipoprotein but lower high-density lipoprotein (+55%, +33% and -13%, respectively; P<.05). Resveratrol normalized food intake, SBP and DBP and prevented obesity and dyslipidemia in EW+Res. EW rats had higher plasma and liver thiobarbituric-acid-reactive substances (TBARS) and lower plasma superoxide dismutase (SOD) and liver glutathione peroxidase activities (+51%, +18%, -58%, -31%, respectively; P<.05), and resveratrol normalized both plasma and liver TBARS and increased the activity of SOD and catalase in plasma. EW rats presented liver steatosis and higher liver TG, and resveratrol prevented these hepatic alterations. In conclusion, this study demonstrated a potential therapeutic use of resveratrol in preventing obesity and oxidative stress and reducing the risk of hypertension, dyslipidemia and steatosis in adult rats programmed by early weaning.

Topics: Animals; Antioxidants; Blood Glucose; Dyslipidemias; Fatty Liver; Female; Glutathione Peroxidase; Hyperphagia; Hypertension; Insulin Resistance; Liver; Obesity; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Stilbenes; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Weaning

Proliferation of pulmonary artery smooth muscle cells (PASMC) is an important contributor to the progress of pulmonary arterial hypertension (PAH). Anti-inflammatory therapies may have therapeutic applicability for PAH. Resveratrol (RES) has prominent anti-inflammatory effects in vitro, but in vivo its beneficial effects are limited by short systemic half life and poor lipotrophy. A derivative of RES, trimethoxystilbene (TMS), has higher lipotropy and extended half life compared with RES, and can potentially overcome the limitations of RES. In the present study, we studied the effects of TMS and RES on proliferation and apoptosis of PASMC stimulated with Tumor Necrosis Factor-α. The effects on PASMC proliferation were quantified by MTT, while apoptosis was assessed by flow cytometry (Annexin V/propidium iodide assay). We observed strong inhibitory effects of TMS on the growth of PASMC, and these effects were 20 times more potent than those of RES. We further documented induction of apoptosis in PASMC treated with TMS, again, to a higher degree than with RES. In conclusion, TMS is more potent than RES in the inhibition of proliferation and induction of apoptosis of PASMC, demonstrating its potentially beneficial role for treating PAH.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Cell Proliferation; Cell Survival; Cells, Cultured; Flow Cytometry; Humans; Hypertension; Inflammation; Male; Myocytes, Smooth Muscle; Pulmonary Artery; Rats; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

The phytoalexin resveratrol (3,4',5-trihydroxy-trans-stilbene) may attenuate cardiovascular disease in man. This study has determined whether treatment with resveratrol (1 mg/kg/day orally) prevented cardiac fibrosis and the decreased cardiovascular function in the DOCA-salt hypertensive rat as a model of human hypertension. Uninephrectomised rats (UNX) administered DOCA (25mg every 4th day sc) and 1% NaCl in drinking water for 28 days developed cardiac and vascular remodelling. In these DOCA-salt rats, resveratrol decreased inflammatory cell infiltration, decreased cardiac fibrosis (left ventricular interstitial and perivascular collagen content) and improved cardiac and vascular function. Resveratrol attenuated other features of cardiovascular remodelling such as increases in systolic blood pressure, left ventricular wet weight, left ventricular wall thickness, diastolic stiffness constant, as well as decreased cardiac contractility and prolonged action potential duration characteristic of DOCA-salt rats. In summary, resveratrol, at a nutritionally relevant dose, prevents or attenuates the adverse changes in the cardiovascular system. We propose that the anti-inflammatory and anti-fibrotic effects of resveratrol are responsible, at least in part, for its amelioration in cardiovascular remodelling in DOCA-salt rats. These actions of resveratrol could play an important role in the protective effects on the human cardiovascular system reported for this constituent of red wine.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Desoxycorticosterone; Fibrosis; Heart; Heart Ventricles; Humans; Hypertension; Male; Mineralocorticoids; Rats; Rats, Wistar; Resveratrol; Sodium Chloride, Dietary; Stilbenes; Ventricular Remodeling

Women are exposed to estrogen in several forms, such as oral contraceptive pills and hormone replacement therapy. Although estrogen was believed to be cardioprotective, lately, its beneficial effects are being questioned. Recent studies indicate that oxidative stress in the rostral ventrolateral medulla (RVLM) may play a role in the development of hypertension. Therefore, we hypothesized that chronic exposure to low levels of estradiol-17β (E(2)) leads to hypertension in adult-cycling female Sprague Dawley (SD) rats potentially through generation of superoxide in the RVLM. To test this hypothesis, young adult (3 or 4 mo old) female SD rats were either sham-implanted or implanted (subcutaneously) with slow-release E(2) pellets (20 ng/day) for 90 days. A group of control and E(2)-treated animals were fed lab chow or chow containing resveratrol (0.84 g/kg of chow), an antioxidant. Rats were implanted with telemeters to continuously monitor blood pressure (BP) and heart rate (HR). At the end of treatment, the RVLM was isolated for measurements of superoxide. E(2) treatment significantly increased mean arterial pressure (mmHg) and HR (beats/min) compared with sham rats (119.6 ± 0.8 vs. 105.1 ± 0.7 mmHg and 371.7 ± 1.5 vs. 354.4 ± 1.3 beats/min, respectively; P < 0.0001). Diastolic and systolic BP were significantly increased in E(2)-treated rats compared with control animals. Superoxide levels in the RVLM increased significantly in the E(2)-treated group (0.833 ± 0.11 nmol/min·mg) compared with control (0.532 ± 0.04 nmol/min·mg; P < 0.05). Treatment with resveratrol reversed the E(2)-induced increases in BP and superoxide levels in the RVLM. In conclusion, these findings support the hypothesis that chronic exposure to low levels of E(2) induces hypertension and increases superoxide levels in the RVLM and that this effect can be reversed by resveratrol treatment.

Topics: Animals; Antioxidants; Blood Pressure; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Estradiol; Estrogens; Heart Rate; Hypertension; Male; Medulla Oblongata; Oxidative Stress; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Superoxides

Endothelial dysfunction is a hallmark of hypertension and vascular oxidative stress can contribute to endothelial dysfunction and hypertension development. Resveratrol is an antioxidant polyphenol which improves endothelium dependent relaxation, the mechanisms of which are unknown. Also, the role of resveratrol in hypertension remains to be established. The purpose of this study was to investigate the mechanisms of resveratrol induced improvement of endothelial function and establish its role in hypertension. SHR and WKY rats, 3-4 weeks old, were treated with resveratrol in drinking water for 10 weeks, untreated SHR and WKY rats served as controls. At the end of the treatment, control SHR exhibited increased blood pressure, oxidative stress and attenuated endothelium dependent relaxation in comparison to WKY rats. The impaired endothelium function in SHR was associated with lower nitrite/nitrate levels, elevated nitrotyrosine content and eNOS uncoupling. Resveratrol treatment attenuated hypertension development in SHR as indicated by lower blood pressure in resveratrol treated SHR (SHR-R) compared to control SHR. SHR-R also exhibited reduced H(2)O(2) content and elevated superoxide dismutase activity. Resveratrol treatment normalized endothelium dependent vasorelaxation in SHR. In parallel, resveratrol restored nitrite/nitrate levels and normalized nitrotyrosine content in SHR. SHR exhibited increased l-arginine dependent superoxide production which was blocked by NOS inhibitor l-NNA, suggesting eNOS uncoupling. eNOS uncoupling was prevented by resveratrol treatment. In conclusion, early treatment with resveratrol lowers oxidative stress, preserves endothelial function and attenuates development of hypertension in SHR. More importantly, prevention of eNOS uncoupling and NO scavenging could represent novel mechanisms for resveratrol-mediated antihypertensive effects.

Topics: Animals; Antioxidants; Blood Pressure; Body Weight; Drinking; Eating; Endothelium, Vascular; Heart; Hypertension; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Organ Size; Oxidative Stress; Rats; Rats, Inbred SHR; Resveratrol; Stilbenes; Tyrosine

Heart failure (HF) is characterized by contractile dysfunction associated with altered energy metabolism. This study was aimed at determining whether resveratrol, a polyphenol known to activate energy metabolism, could be beneficial as a metabolic therapy of HF. Survival, ventricular and vascular function as well as cardiac and skeletal muscle energy metabolism were assessed in a hypertensive model of HF, the Dahl salt-sensitive rat fed with a high-salt diet (HS-NT). Resveratrol (18 mg/kg/day; HS-RSV) was given for 8 weeks after hypertension and cardiac hypertrophy were established (which occurred 3 weeks after salt addition). Resveratrol treatment improved survival (64% in HS-RSV versus 15% in HS-NT, p<0.001), and prevented the 25% reduction in body weight in HS-NT (P<0.001). Moreover, RSV counteracted the development of cardiac dysfunction (fractional shortening -34% in HS-NT) as evaluated by echocardiography, which occurred without regression of hypertension or hypertrophy. Moreover, aortic endothelial dysfunction present in HS-NT was prevented in resveratrol-treated rats. Resveratrol treatment tended to preserve mitochondrial mass and biogenesis and completely protected mitochondrial fatty acid oxidation and PPARα (peroxisome proliferator-activated receptor α) expression. We conclude that resveratrol treatment exerts beneficial protective effects on survival, endothelium-dependent smooth muscle relaxation and cardiac contractile and mitochondrial function, suggesting that resveratrol or metabolic activators could be a relevant therapy in hypertension-induced HF.

Topics: Animals; Body Weight; Disease Models, Animal; Endothelium, Vascular; Energy Metabolism; Heart; Heart Failure; Hemodynamics; Hypertension; Male; Mitochondria; Rats; Rats, Inbred Dahl; Resveratrol; Signal Transduction; Stilbenes; Survival Analysis

Cardiac hypertrophy is a compensatory enlargement of the heart in response to stress such as hypertension. It is beneficial in reducing stress placed on the heart. However, when the stress is of a chronic nature, it becomes pathological and leads to cardiac dysfunction and heart failure. Current treatments for hypertension and heart failure have proven beneficial but are not highly specific and associated with side effects. Accordingly, there is an important need for alternative strategies to provide safe and effective treatment.. Ten-week-old male spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were treated with resveratrol (2.5 mg/kg/day) for a period of 10 weeks. Systolic blood pressure, and cardiac structure and function were measured in all groups at different time points of resveratrol treatment. Oxidative stress was also determined in all groups after 10 weeks of resveratrol treatment.. SHRs were characterized with high blood pressure and concentric hypertrophy from 15 weeks of age. Cardiac functional abnormalities were also evident in SHR from 15 weeks onwards. Resveratrol treatment significantly prevented the development of concentric hypertrophy, and systolic and diastolic dysfunction in SHR without lowering blood pressure. Resveratrol also significantly reduced the oxidative stress levels of cardiac tissue in SHR.. Resveratrol treatment was beneficial in preventing the development of concentric hypertrophy and cardiac dysfunction in SHR. The cardioprotective effect of resveratrol in SHR may be partially mediated by a reduction in oxidative stress. Thus, resveratrol may have potential in preventing cardiac impairment in patients with essential hypertension.

Topics: Aging; Animals; Antioxidants; Blood Pressure; Cardiomegaly; Echocardiography; Heart Function Tests; Hypertension; Lipid Peroxidation; Male; Myocardial Contraction; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Resveratrol; Stilbenes

Topics: Animals; Antioxidants; Cardiomegaly; Cardiotonic Agents; Chronic Disease; Heart Diseases; Heart Failure; Hypertension; Myocardial Contraction; Rats; Rats, Inbred SHR; Resveratrol; Stilbenes

There is compelling evidence to indicate an important role for increased local renin-angiotensin system activity in the pathogenesis of cardiac hypertrophy and heart failure. Resveratrol is a natural polyphenol that activates SIRT1, a novel cardioprotective and longevity factor having NAD(+)-dependent histone deacetylase activity. We tested the hypothesis whether resveratrol could prevent from angiotensin II (Ang II)-induced cardiovascular damage. Four-week-old double transgenic rats harboring human renin and human angiotensinogen genes (dTGR) were treated for 4 weeks either with SIRT1 activator resveratrol or SIRT1 inhibitor nicotinamide. Untreated dTGR and their normotensive Sprague-Dawley control rats (SD) received vehicle. Untreated dTGR developed severe hypertension as well as cardiac hypertrophy, and showed pronounced cardiovascular mortality compared with normotensive SD rats. Resveratrol slightly but significantly decreased blood pressure, ameliorated cardiac hypertrophy and prevented completely Ang II-induced mortality, whereas nicotinamide increased blood pressure without significantly influencing cardiac hypertrophy or survival. Resveratrol decreased cardiac ANP mRNA expression and induced cardiac mRNA expressions of mitochondrial biogenesis markers peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha), mitochondrial transcription factor (Tfam), nuclear respiratory factor 1 (NRF-1) and cytochrome c oxidase subunit 4 (cox4). Resveratrol dose-dependently increased SIRT1 activity in vitro. Our findings suggest that the beneficial effects of SIRT1 activator resveratrol on Ang II-induced cardiac remodeling are mediated by blood pressure-dependent pathways and are linked to increased mitochondrial biogenesis.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Cardiomegaly; Genes; Heart; Humans; Hypertension; Male; Mitochondria; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renin; Renin-Angiotensin System; Resveratrol; Stilbenes

Small arteries from the spontaneously hypertensive rat (SHR) exhibit abnormal stiffness and geometry. This study investigated the effects of resveratrol, a polyphenol found in foods such as red grapes, on small arteries in SHR.. Wistar-Kyoto (WKY) rats and SHR were treated with resveratrol (2.5 mg/kg/day) for 10 weeks. Mesenteric small artery segments (third-order branches) were mounted in a pressure myograph, and vascular geometry and mechanical properties were calculated from lumen and media dimensions measured at incremental intraluminal pressures. Systolic blood pressure was measured by tail-cuff plethysmography.. Increased compliance and reduced wall component stiffness were observed in SHR arteries vs. WKY arteries. Though resveratrol did not prevent lowering of wall component stiffness, it did attenuate, at least in part, the increased compliance of SHR arteries. In contrast, resveratrol increased compliance and reduced wall component stiffness in WKY arteries. SHR arteries exhibited remodeling that consisted of narrowed lumens, thickened media widths, and augmented media-to-lumen ratios. Resveratrol partially attenuated the remodeling process and also abolished exaggerated ERK signaling and expression of proliferating cell nuclear antigen (a marker of proliferation) in SHR arteries. The latter effects might be related to the ability of resveratrol to alleviate oxidative stress in SHR and enhance protein kinase G (PKG) activity. Elevated blood pressure in 20-week-old SHR was unaffected by resveratrol.. The ability of resveratrol to limit the increase in compliance of SHR arteries is likely related to inhibitory effects on remodeling and pro-growth ERK signaling rather than blood pressure or arterial wall component stiffness.

Topics: Aging; Animals; Blood Pressure; Compliance; Hypertension; Male; Mesenteric Arteries; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Resveratrol; Stilbenes; Vascular Resistance

Hypertension is the leading cause of cardiovascular diseases, and angiotensin II is one of the major components of the mechanisms that contribute to the development of hypertension. However, the precise mechanisms for the development of hypertension are unknown. Our recent study showing that angiotensin II-induced vascular smooth muscle cell growth depends on cytochrome P450 1B1 led us to investigate its contribution to hypertension caused by this peptide. Angiotensin II was infused via miniosmotic pump into rats (150 ng/kg per minute) or mice (1000 μg/kg per day) for 13 days resulting in increased blood pressure, increased cardiac and vascular hypertrophy, increased vascular reactivity to vasoconstrictor agents, increased vascular reactive oxygen species production, and endothelial dysfunction in both species. The increase in blood pressure and associated pathophysiological changes were minimized by the cytochrome P450 1B1 inhibitor 2,3',4,5'-tetramethoxystilbene in both species and was markedly reduced in Cyp1b1(-/-) mice. These data suggest that cytochrome P450 1B1 contributes to angiotensin II-induced hypertension and associated pathophysiological changes. Moreover, 2,3',4,5'-tetramethoxystilbene, which prevents both cytochrome P450 1B1-dependent and -independent components of angiotensin II-induced hypertension and inhibits associated pathophysiological changes could be clinically useful in the treatment of hypertension and associated cardiovascular and inflammatory diseases.

Topics: Angiotensin II; Animals; Aorta; Aryl Hydrocarbon Hydroxylases; Blood Pressure; Blotting, Western; Cardiomegaly; Cytochrome P-450 CYP1B1; Endothelium, Vascular; Hypertension; Infusions, Intravenous; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinases; Myocardium; NADPH Oxidases; Organ Size; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Stilbenes; Vasoconstrictor Agents

Reactive oxygen species (ROS) contribute to various models of hypertension, including deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Recently, we have shown that ROS, generated by cytochrome P-450 1B1 (CYP1B1) from arachidonic acid, mediate vascular smooth muscle cell growth caused by angiotensin II. This study was conducted to determine the contribution of CYP1B1 to hypertension and associated pathophysiological changes produced by DOCA (30 mg/kg) given subcutaneously per week with 1% NaCl + 0.1% KCl in drinking water to uninephrectomized rats for 6 wk. DOCA-salt treatment increased systolic blood pressure (SBP). Injections of the selective inhibitor of CYP1B1, 2,3',4,5'-tetramethoxystilbene (TMS; 300 μg/kg ip every 3rd day) initiated at the 4th week of DOCA-salt treatment normalized SBP and decreased CYP1B1 activity but not its expression in the aorta, heart, and kidney. TMS also inhibited cardiovascular and kidney hypertrophy, prevented the increase in vascular reactivity and endothelial dysfunction, and minimized the increase in urinary protein and K(+) output and the decrease in urine osmolality, Na(+) output, and creatinine clearance associated with DOCA-salt treatment. These pathophysiological changes caused by DOCA-salt treatment and associated increase in vascular superoxide production, NADPH oxidase activity, and expression of NOX-1, and ERK1/2 and p38 MAPK activities in the aorta, heart, and kidney were inhibited by TMS. These data suggest that CYP1B1 contributes to DOCA-salt-induced hypertension and associated pathophysiological changes, most likely as a result of increased ROS production and ERK1/2 and p38 MAPK activity, and could serve as a novel target for the development of agents like TMS to treat hypertension.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Antihypertensive Agents; Aorta; Aryl Hydrocarbon Hydroxylases; Blood Pressure; Cardiomegaly; Cytochrome P-450 CYP1B1; Desoxycorticosterone; Disease Models, Animal; Diuresis; Endothelium, Vascular; Enzyme Inhibitors; Hydroxyeicosatetraenoic Acids; Hypertension; Kidney; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle, Smooth, Vascular; Myocardium; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; p38 Mitogen-Activated Protein Kinases; Proteinuria; Rats; Rats, Sprague-Dawley; Sodium Chloride, Dietary; Stilbenes; Superoxides; Time Factors; Vasoconstriction; Vasodilation

Resveratrol is a natural polyphenolic stilbene derivative found in several human diet components that possess important and wide-ranging effects in biological systems including anticancer, anti-inflammatory, antioxidant, cardio-protective, and anti-ageing actions and beneficial properties against metabolic diseases. This study addresses the effects of long-term administration of resveratrol on several functional alterations arising from the metabolic syndrome experimental model of obese Zucker rats, and the possible mechanisms involved. The high plasma concentrations of triglycerides, total cholesterol, free fatty acids, insulin and leptin found in obese Zucker rats were reduced in obese rats that received resveratrol. Furthermore, the elevated hepatic lipid content was significantly lower in obese rats treated with resveratrol, an effect which was related to the increased phosphorylation of 5'-AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in the liver of these animals. Resveratrol treatment also improved the inflammatory status peculiar to this model, as it increased the concentration of adiponectin and lowered tumor necrosis factor-alpha production in the visceral adipose tissue (VAT) of obese Zucker rats. Moreover, chronic intake of resveratrol enhanced VAT eNOS expression among obese Zucker rats. These effects parallel the activation of AMPK and inhibition by phosphorylation of ACC in this tissue. The raised systolic blood pressure and reduced aortic eNOS expression found in obese Zucker rats were significantly improved in the resveratrol-treated obese rats. In conclusion, resveratrol improved dyslipidemia, hyperinsulinemia, hyperleptinemia and hypertension in obese Zucker rats, and produced anti-inflammatory effects in VAT, effects that seem to be mediated by AMPK activation.

Topics: Adipose Tissue; Animals; Blood Pressure; Disease Models, Animal; Drug Administration Schedule; Humans; Hypertension; Lipid Metabolism; Male; Metabolic Syndrome; Obesity; Random Allocation; Rats; Rats, Zucker; Resveratrol; Stilbenes

Master regulators of protein synthesis such as mammalian target of rapamycin (mTOR) and p70S6 kinase contribute to left ventricular hypertrophy. These prohypertrophic pathways are modulated by a number of kinase cascades, including the hierarchical LKB1/AMP-activated protein kinase (AMPK) energy-sensing pathway. Because oxidative stress inhibits the LKB1/AMPK signaling axis to promote abnormal cell growth in cancer cells, we investigated whether oxidative stress associated with hypertension also results in the inhibition of this kinase circuit to contribute to left ventricular hypertrophy.. In the spontaneously hypertensive rat, a well-established genetic model of hypertension and subsequent cardiac hypertrophy, the development of left ventricular hypertrophy is associated with an increase in the electrophilic lipid peroxidation byproduct 4-hydroxy-2-nonenal (HNE). Using isolated cardiomyocytes, we show that elevated levels of HNE result in the formation of HNE-LKB1 adducts that inhibit LKB1 and subsequent AMPK activity. Consistent with inhibition of the LKB1/AMPK signaling pathway, the mTOR/p70S6 kinase system is activated, which is permissive for cardiac myocyte cell growth. Treatment of cardiomyocytes with resveratrol prevents HNE modification of the LKB1/AMPK signaling axis and blunts the prohypertrophic p70S6 kinase response. Furthermore, administration of resveratrol to spontaneously hypertensive rats results in increased AMPK phosphorylation and activity and reduced left ventricular hypertrophy.. Our data identify a molecular mechanism in the cardiomyocyte involving the oxidative stress-derived lipid peroxidation byproduct HNE and the LKB1/AMPK signaling pathway that contributes to the development of left ventricular hypertrophy. We also suggest that resveratrol may be a potential therapy for patients at risk for developing pathological cardiac hypertrophy by preventing this prohypertrophic process.

Topics: Aldehydes; AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Cardiomegaly; Cells, Cultured; Hypertension; Hypertrophy, Left Ventricular; Lipid Peroxidation; Myocytes, Cardiac; Oxidative Stress; Protein Kinases; Protein Serine-Threonine Kinases; Rats; Rats, Inbred SHR; Resveratrol; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Stilbenes; TOR Serine-Threonine Kinases

Experimental NO deficiency induced by L-NAME injection led to the development of arterial hypertension, endothelial dysfunction, and cardiomyocyte hypertrophy and reduced blood content of nitrates and nitrites. Impaza, NO donors, activators of NO-synthase, antioxidants, and antihypertensive preparations produced endothelium-protective effect of different degree.

Topics: Animals; Antibodies; Antihypertensive Agents; Antioxidants; Endothelium, Vascular; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitrites; Rats; Rats, Wistar; Resveratrol; Stilbenes

Resveratrol (3,5,4'-trihydroxystilbene), a polyphenol found in red wine, is known to activate sirtuin1 (SIRT1), a longevity gene. Previous studies have demonstrated that resveratrol extends the life span of diverse species through activation of SIRT1. It was also reported that inhibition of angiotensin II function by angiotensin II type I receptor (AT1R) antagonist prolonged rat life span. We, therefore, hypothesized that resveratrol may inhibit the renin-angiontein system and examined whether resveratrol affects AT1R expression in vascular smooth muscle cells (VSMCs).. Northern and Western blot analysis revealed that resveratrol significantly decreased the expression of AT1R at mRNA and protein levels in a dose- and time-dependent manner. Overexpression of SIRT1 reduced AT1R expression whereas nicotinamide, an inhibitor of SIRT1, increased AT1R expression and reversed the resveratrol-induced AT1R downregulation. AT1R gene promoter activity was decreased by resveratrol, but resveratrol did not affect the AT1R mRNA stability. Deletion analysis showed that the most proximal region of AT1R gene promoter containing Sp1 site is responsible for downregulation. Administration of resveratrol suppressed AT1R expression in the mouse aorta and blunted angiotensin II-induced hypertension.. Resveratrol suppressed AT1R expression through SIRT1 activation both in vivo and in vitro. The inhibition of the renin-angiotensin system may contribute, at least in part, to the resveratrol-induced longevity and antiatherogenic effect of resveratrol.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Aorta; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Inhibitors; Hypertension; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Niacinamide; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Resveratrol; RNA, Messenger; Sirtuin 1; Sirtuins; Sp1 Transcription Factor; Stilbenes; Time Factors; Transcription, Genetic; Transfection

This study was designed to examine the effects of the antioxidant resveratrol on cardiac structure and function in pressure overload (PO)-induced cardiac hypertrophy. Male Sprague-Dawley rats were subjected to sham operation and the aortic banding procedure. A subgroup of sham control and aortic-banded rats were treated with resveratrol for 2 wk after surgery. Echocardiographic analysis of cardiac structure and function along with Western blot analysis of endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and redox factor-1 (ref-1) were performed in all groups after 4 wk of surgery. Banded rats showed significantly increased left ventricle-to-body weight ratio. Echocardiographic analysis showed that the interventricular septal wall thickness and left ventricular posterior wall thickness at systole and diastole were significantly increased in banded rats. Also, a significant increase in isovolumic relaxation time was observed in banded rats. Measured eNOS, iNOS, and ref-1 protein levels were significantly reduced in banded rats. Resveratrol treatment prevented the above changes in cardiac structure, function, and protein expression in banded rats. Aortic banding after 4 wk resulted in concentric remodeling and impaired contractile function due to PO on the heart. The 2-wk treatment with resveratrol was found to abolish PO-induced cardiac hypertrophy. Resveratrol may therefore be beneficial against PO-induced cardiac hypertrophy found in clinical settings of hypertension and aortic valve stenosis.

Topics: Animals; Aorta; Dose-Response Relationship, Drug; Hypertension; Hypertrophy, Left Ventricular; Male; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Resveratrol; Stilbenes; Stroke Volume; Treatment Outcome; Ultrasonography; Vasodilator Agents; Ventricular Dysfunction, Left

Spontaneously hypertensive rats (SHRs) were administered the red wine polyphenol resveratrol in drinking water at 0, 0.448, or 4.48 mg/l (control, low, or high, respectively) for 28 days. The low dosage was chosen to mimic moderate red wine consumption. After the treatment period, thoracic aorta rings were excised for in vitro assessment of vasomotor function. Chronic resveratrol significantly improved endothelium-dependent relaxation to acetylcholine (Ach), increasing maximal values to 80.8% +/- 5.2% and 80.8% +/- 5.0% in low and high groups, respectively, compared with 60.7% +/- 1.4% in controls (P<0.01). This treatment effect was eliminated in the presence of the endothelial nitric oxide synthase (eNOS) blocker N(omega)-nitro-L-arginine methyl ester. Resveratrol did not affect relaxation to sodium nitroprusside or systolic blood pressure in SHRs. In contrast to the SHR results, chronic resveratrol in Sprague Dawley rats did not affect vasomotor function in aorta rings in response to Ach. Hydrogen peroxide was reduced in the SHR thoracic aorta by a high dosage of resveratrol (P<0.05), but it was not significantly altered in other tissues tested. Thoracic aorta immunoblots revealed no significant treatment effects in SHRs on eNOS, superoxide dismutases 1 and 2, gp91phox, or Hsp90. Thus, these data provide novel evidence of improved endothelium-dependent vasorelaxation in hypertensive, but not normotensive, animals as a result of chronic resveratrol consumption mimicking dosages resulting from moderate red wine consumption. This response was not dependent on increases in eNOS expression but was dependent on improved NO bioavailability.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Endothelium; Hydrogen Peroxide; Hypertension; Kidney; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type III; Nitroprusside; Rats; Rats, Inbred SHR; Reactive Oxygen Species; Resveratrol; Stilbenes; Vasodilation; Vasodilator Agents

We studied the effects of antioxidants resveratrol and pQ510 on physiological parameters and the state of endothelial NO-synthase as a marker of the regulatory function of the endothelium in the aorta of rats with modeled arterial hypertension. The antioxidants promoted recovery of stable NO metabolites in rat serum and maintained expression of endothelial NO-synthase at a normal level. These effects were confirmed by correction of blood pressure and endothelium-dependent vascular dilation assessed by endothelial dysfunction coefficient.

Topics: Animals; Antioxidants; Ascorbic Acid; Endothelium, Vascular; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Organometallic Compounds; Rats; Rats, Wistar; Resveratrol; Stilbenes

There seems to be a link between the cluster of risk factors known as insulin resistance syndrome with endothelial dysfunction. Resveratrol (3,4,5-trihydroxyestilbene) (RV), an antioxidant found in many components of the human diet, has been proposed as an effective agent in the prevention of several pathologic processes. This study examined the effect of chronic administration of RV on endothelial nitric oxide synthase (eNOS) activity in cardiovascular tissues and on plasma lipid peroxidation in fructose-fed rats (FFR), an experimental model of this syndrome.. Male Sprague Dawley rats were separated into four groups: Control, Control + RV, FFR, and FFR + RV (n = 8 in each group). The RV (10 mg/kg/d by gavage) and fructose (10% in drinking water) were administered for 45 days. Metabolic variables and systolic blood pressure (BP) were measured. The eNOS activity was estimated in the mesenteric arterial bed and cardiac tissue homogenates by conversion of (3)H-arginine to (3)H-citrulline. Lipid peroxidation was estimated through the measurement of plasmatic thiobarbituric acid-reactive substances (TBARS).. The RV chronic treatment prevented the increase in systolic BP and cardiac hypertrophy, restored FFR mesenteric and cardiac eNOS activities, and decreased the elevated TBARS levels that characterize FFR, without an effect on other metabolic variables.. In concert with other effects, the increase in eNOS activity may contribute to the protective properties attributed to RV and, thus, to its beneficial effects on the cardiovascular system. These results suggest that an adequate supplementation of RV might help to prevent or delay the occurrence of atherogenic cardiovascular diseases associated to insulin-resistant states.

Topics: Administration, Oral; Animal Feed; Animals; Antioxidants; Arteriosclerosis; Biomarkers; Blood Pressure; Follow-Up Studies; Fructose; Heart Ventricles; Hypertension; Insulin Resistance; Lipid Peroxidation; Male; Mesenteric Arteries; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Resveratrol; Risk Factors; Spectrophotometry; Stilbenes; Sweetening Agents; Thiobarbituric Acid Reactive Substances; Time Factors

To investigate the effect of trans-resveratrol on hypertension-induced cardiac hypertrophy and its potential mechanisms involving endothelin (ET), angiotensin II (AngII) and nitric oxide (NO).. Animal models bearing cardiac hypertrophy were replicated in male SD rats following partially nephrectomy (PNX). 10 mg/kg bw or 50 mg/kg bw of resveratrol was administered to rats by gavage, respectively, for 4 weeks. PNX control and sham-operation control (SHAM) were simultaneously established. Systolic pressure of rats was measured through tail at baseline and it, as well as heart weight, was measured after 4-week treatment. Serum ET-1 and AngII concentrations were determined using radioimmunological assay and NO using nitric acid reductase method.. After 4-week treatment, animals in PNX control group had significantly higher systolic pressure and heart weight, higher ET-1 and AngII concentrations while lower NO concentrations, compared with those in SHAM group (P < 0.05). Rats treated with 50 mg/kg bw of resveratrol had significantly lower systolic pressure and heart weight, lower ET-1 concentrations while higher NO concentrations, compared with animals in PNX group (P < 0.05).. Trans-resveratrol could protect against the increase of systonic pressure and subsequent cardiac hypertrophy in vivo, which mechanisms might, at least partly, involve with its modulation on NO, AngII and ET.

Topics: Angiotensin II; Animals; Cardiomegaly; Cardiovascular Agents; Endothelin-1; Hypertension; Male; Myocardium; Nephrectomy; Nitric Oxide; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

We examined the effect of resveratrol (3,4',5-trihydroxy stilbene), a phenolic compound found in the skins of most grapes, on blood pressure and bone loss in ovariectomized (OVX), stroke-prone spontaneously hypertensive rats (SHRSP). Nineteen-week-old female SHRSP were divided into a sham-ovariectomized (sham) group fed a control diet and two OVX groups fed either a control diet (OVX-Cont) or a diet supplemented with resveratrol (5 mg/kg per d; OVX-Resv). Ovariectomy induced significant increases in systolic blood pressure (SBP). Resveratrol lowered the SBP by 15%) by the third week of administration, and this effect was maintained throughout the study. Resveratrol treatment also significantly enhanced endothelium-dependent vascular relaxation in response to acetylcholine (ACh) in OVX rats. Finally, femur breaking energies measured for the resveratrol-treated (OVX-Resv) group were significantly higher than those of the resveratrol-untreated (OVX-Cont) group. While no significant differences in calcium, magnesium and phosphorus content were found between the femurs of OVX-Cont and OVX-Resv rats, the femur hydroxyproline content in the OVX-Resv group was significantly higher than of the OVX-Cont group. We conclude that, in OVX-SHRSP, resveratrol acts by a similar mechanism to mammalian estrogens, lowering blood pressure by increasing dilatory responses to ACh. The present study also demonstrated that resveratrol was able to prevent ovariectomy-induced decreases in femoral bone strength.

Topics: Animals; Antihypertensive Agents; Bone Density; Disease Models, Animal; Female; Femur; Hypertension; Osteoporosis; Ovariectomy; Rats; Rats, Inbred SHR; Resveratrol; Stilbenes

A recent study demonstrated that reactive oxygen species (ROS) were involved in the maintenance of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). However, the role of oxidative stress in hypertension and its related diseases in SHRSP remains unknown. To determine whether phytoestrogens attenuate oxidative DNA damage in vascular smooth muscle cells (VSMC) from SHRSP and Wistar-Kyoto (WKY) rats, we investigated the effect of daidzein, genistein and resveratrol on oxidative DNA damage in VSMC, induced by advanced glycation end-products (AGEs).. VSMC were treated with AGEs in the presence or absence of phytoestrogens for the indicated time. Cellular degeneration induced by AGEs was characterized in terms of intracellular oxidant levels, intracellular total glutathione (GSH) levels, mRNA expression for gamma-glutamylcysteine synthetase (GCS), and a new marker of oxidative stress, 8-hydroxy-2'-deoxyguanosine (8-OHdG) contents.. AGEs stimulated 8-OHdG formation in VSMC in a time- and dose-dependent manner. We also confirmed that VSMC from SHRSP were more vulnerable to oxidative stress induced by AGEs, than VSMC from WKY rats. Daidzein, genistein or resveratrol reduced AGEs-induced 8-OHdG formation in a dose-dependent manner. The preventive effects of phytoestrogens on 8-OHdG formation remarkably paralleled changes in the intracellular oxidant levels in VSMC following AGEs treatment. We further demonstrated that phytoestrogens increase intracellular total GSH level in VSMC. Increased GSH synthesis was due to enhanced expression of the rate-limiting enzyme for GSH synthesis, GCS. Phytoestrogens-stimulated total GSH level in VSMC could lead to decreased intracellular oxidant levels, and thus prevent oxidative DNA damage, induced by AGEs. The phytoestrogens are powerful antioxidants able to interfere with AGEs-mediated oxidative DNA damage of VSMC, and are potentially useful against vascular diseases where ROS are involved in hypertension.

Topics: Animals; Base Sequence; Cells, Cultured; DNA Damage; DNA Primers; Estrogens, Non-Steroidal; Genistein; Glutathione; Glutathione Peroxidase; Glycation End Products, Advanced; Hypertension; Isoflavones; Muscle, Smooth, Vascular; Oxidation-Reduction; Oxidative Stress; Phytoestrogens; Plant Preparations; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reactive Oxygen Species; Resveratrol; RNA, Messenger; Stilbenes; Stroke

In order to investigate the membrane-located mechanisms that control intracellular pH in resistance arteries, mesenteric vessels from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at 5 weeks of age were mounted in a myograph and loaded with 2',7'-bis(carboxyethyl)5,6-carboxyfluorescein (BCECF). Resting intracellular pH was studied over 10 min in the presence of amiloride (1 mmol/l), or 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS; 0.2 mmol/l). In the presence of DIDS, there was no significant difference in the resulting fall in intracellular pH over 10 min between rat strains. However, in the presence of amiloride there was a significantly greater fall in intracellular pH in SHR (P less than 0.001). These data indicate that in the resting state Na(+)-H+ exchange is increased in SHR resistance arteries at the time when blood pressure is rising and vascular remodelling is taking place.

Topics: 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; Amiloride; Animals; Fluoresceins; Fluorescent Dyes; Hydrogen-Ion Concentration; Hypertension; In Vitro Techniques; Male; Mesenteric Arteries; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stilbenes; Vascular Resistance

Opening of the blood-brain barrier (BBB) by a hypertensive insult comprises the formation of endothelial micropinocytosis. Constricted vessels are less vulnerable to the insult. In the present study SITS (4-acetamido-4'-isothiocyano-stilbene-2,2'-disulfonic acid disodium) was shown to prevent leakage across the BBB into the brain parenchyma following a hypertensive insult induced by a local increase of the intraluminal pressure in anesthetized rats and by i.v. administration of adrenaline or bicuculline in conscious unrestrained animals. Since SITS induced an increase in cerebral blood flow the protection cannot be explained by a constrictory action on the cerebral vessels. SITS is a drug with complex action on the cell membrane including an inhibitory effect on anion transport mechanisms and on some c-AMP mediated processes. It is possible that the protection of BBB observed in the present study is connected to a reduction of c-AMP but membrane stabilizing effect can at present not be excluded.

Topics: 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; Animals; Bicuculline; Blood-Brain Barrier; Cell Membrane; Cerebrovascular Circulation; Cyclic AMP; Epinephrine; Hypertension; Male; Pinocytosis; Rats; Stilbenes

Acute experimental hypertension induces protein leakage in the brain. The protein is thought to be, at least to a great extent, transported through the endothelial cells by pinocytosis. An anion transport inhibitor, 4 acetamido-4-isothiocyano-stilbene-2,2'-disulfonic acid, markedly reduced adrenaline or bicuculline-induced leakage of 125IHSA and Evans blue-albumin in all areas of the rat brain. The preventive effect of dexamethasone was less pronounced and no effect was seen of haloperidol.

Topics: Acute Disease; Animals; Anions; Bicuculline; Blood Proteins; Blood-Brain Barrier; Cerebrospinal Fluid Proteins; Dexamethasone; Endothelium; Epinephrine; Haloperidol; Hypertension; Male; Pinocytosis; Rats; Serum Albumin, Radio-Iodinated; Stilbenes

Topics: Adrenal Cortex Hormones; Adult; Androgens; Arteriosclerosis; Clofibrate; Coronary Disease; Female; Humans; Hypertension; Hypopituitarism; Nitroglycerin; Pregnancy; Puerperal Disorders; Radiography; Renal Artery Obstruction; Stilbenes; Thyroid Hormones

Topics: Adrenocorticotropic Hormone; Aldosterone; Animals; Arginine Vasopressin; Blood Pressure; Body Weight; Cortisone; Desoxycorticosterone; Hormones; Hypertension; Norepinephrine; Progesterone; Rats; Rats, Inbred SHR; Research; Sodium Chloride; Spironolactone; Stilbenes; Testosterone; Thyroid Hormones; Vasopressins

Topics: Adenosine Triphosphate; Cardiomyopathies; Disease; Heart Diseases; Humans; Hypertension; Inositol; Myocardium; Stilbenes