The efficacy of resveratrol in controlling hypertension: study protocol for a randomized, crossover, double-blinded, placebo-controlled trial

Abstract Background: 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. Methods/design: 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. Discussion: 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. Trial registration: Iranian Registry of Clinical Trials, IRCT201407078129N7. Registered on 15 August 2014. Keywords: Resveratrol, Hypertension, Blood pressure, Polypheno

Are the cardioprotective effects of the phytoestrogen resveratrol sex dependent?

Cardiovascular disease (CVD) is the number one cause of death in both men and women. Younger women have a lower risk for CVD, but their risk increases considerably after menopause when estrogen levels decrease. The cardiovascular protective properties of estrogen are mediated through decreasing vascular inflammation and progression of atherosclerosis, decreasing endothelial cell damage by preventing apoptosis and anti-hypertrophic mechanisms. Estrogen also regulates glucose and lipid levels which are two important risk factors for CVD. Resveratrol (RES), a cardioprotective polyphenolic compound is classified as a phytoestrogen due its capacity to bind to and modulate estrogen receptor signaling. Due to its estrogen like property, we speculate that the cardioprotective effects of RES treatment could be sex dependent. Based on earlier reports and more recent data from our lab presented here, we found that RES treatment may have more favourable cardiovascular outcomes in females when compared to males. This review will discuss estrogen and phytoestrogens such as RES, mediated cardioprotection with a specific focus on sex dependent effects reported in preclinical and clinical studies.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Comparative and Combinatorial Effects of Resveratrol and Sacubitril/Valsartan alongside Valsartan on Cardiac Remodeling and Dysfunction in MI-Induced Rats

The development and progression of heart failure (HF) due to myocardial infarction (MI) is a major concern even with current optimal therapy. Resveratrol is a plant polyphenol with cardioprotective properties. Sacubitril/valsartan is known to be beneficial in chronic HF patients. In this study, we investigated the comparative and combinatorial benefits of resveratrol with sacubitril/valsartan alongside an active comparator valsartan in MI-induced male Sprague Dawley rats. MI-induced and sham-operated animals received vehicle, resveratrol, sacubitril/valsartan, valsartan alone or sacubitril/valsartan + resveratrol for 8 weeks. Echocardiography was performed at the endpoint to assess cardiac structure and function. Cardiac oxidative stress, inflammation, fibrosis, brain natriuretic peptide (BNP), creatinine and neutrophil gelatinase associated lipocalin were measured. Treatment with resveratrol, sacubitril/valsartan, valsartan and sacubitril/valsartan + resveratrol significantly prevented left ventricular (LV) dilatation and improved LV ejection fraction in MI-induced rats. All treatments also significantly reduced myocardial tissue oxidative stress, inflammation and fibrosis, as well as BNP. Treatment with the combination of sacubitril/valsartan and resveratrol did not show additive effects. In conclusion, resveratrol, sacubitril/valsartan, and valsartan significantly prevented cardiac remodeling and dysfunction in MI-induced rats. The reduction in cardiac remodeling and dysfunction in MI-induced rats was mediated by a reduction in cardiac oxidative stress, inflammation and fibrosis

The Effects of Resveratrol in Patients with Cardiovascular Disease and Heart Failure: A Narrative Review

Cardiovascular disease (CVD) is the main cause of death globally and responsible for the second highest number of deaths in Canada. Medical advancements in the treatment of CVD have led to patients living longer with CVD but often progressing to another condition called heart failure (HF). As a result, HF has emerged in the last decade as a major medical concern. Fortunately, various “traditional„ pharmacotherapies for HF exist and have shown success in reducing HF-associated mortality. However, to augment the treatment of patients with CVD and/or HF, alternative pharmacotherapies using nutraceuticals have also shown promise in the prevention and treatment of these two conditions. One of these natural compounds considered to potentially help treat HF and CVD and prevent their development is resveratrol. Herein, we review the clinical findings of resveratrol’s ability to be used as an effective treatment to potentially help treat HF and CVD. This will allow us to gain a more fulsome appreciation for the effects of resveratrol in the health outcomes of specific patient populations who have various disorders that constitute CVD

Potential Associations among Bioactive Molecules, Antioxidant Activity and Resveratrol Production in <i>Vitis vinifera</i> Fruits of North America

Grapes (Vitis vinifera L.) are rich in bioactive molecules contributing to health benefits. Consumption of grapes is linked to reduced incidence of cardiovascular diseases. Studies on table grape cultivars are limited although much attention in research was focused on the wine industry. Bioactive effects of grapes as anti-inflammatory, anticarcinogenic, cardioprotective, vasorelaxant, phytoestrogenic and neuroprotective have also been reported. For example, resveratrol is a natural food ingredient present in grapes, with high antioxidant potential. Here we conducted an exploratory study to investigate bioactive molecules, antioxidant activity and the association between constitutive stilbene synthase (STS) gene expression and the resveratrol biosynthesis in selected table grape varieties in North America. The phenolic compounds, fatty acid composition and antioxidant activity of four grape varieties were compared. Red Globe variety was rich in unsaturated fatty acids as well as phenolic compounds such as caffeic acid, quercetin and resveratrol. Meanwhile, the constitutive expression of grape stilbene synthase gene was higher in Flame and Autumn Royal where resveratrol content of these cultivars was relatively low compared to the Red Globe variety. This study shows the potential links in grape antioxidant activity and resveratrol production, but more studies are necessary to show the association

A Novel Hemp Seed Meal Protein Hydrolysate Reduces Oxidative Stress Factors in Spontaneously Hypertensive Rats

This report shows the antioxidant effects of a hemp seed meal protein hydrolysate (HMH) in spontaneously hypertensive rats (SHR). Defatted hemp seed meal was hydrolyzed consecutively with pepsin and pancreatin to yield HMH, which was incorporated into rat feed as a source of antioxidant peptides. Young (8-week old) SHRs were divided into three groups (8 rats/group) and fed diets that contained 0.0%, 0.5% or 1.0% (w/w) HMH for eight weeks; half of the rats were sacrificed for blood collection. After a 4-week washout period, the remaining 20-week old SHRs were fed for an additional four weeks and sacrificed for blood collection. Plasma total antioxidant capacity (TAC) and superoxide dismutase (SOD), catalase (CAT) and total peroxides (TPx) levels were determined. Results showed that plasma TAC, CAT and SOD levels decreased in the older 20-week old SHRs when compared to the young SHRs. The presence of HMH in the diets led to significant (p &lt; 0.05) increases in plasma SOD and CAT levels in both young and adult SHR groups; these increases were accompanied by decreases in TPx levels. The results suggest that HMH contained antioxidant peptides that reduced the rate of lipid peroxidation in SHRs with enhanced antioxidant enzyme levels and total antioxidant capacity

Effects of N-acetyl cysteine and melatonin on early reperfusion injury in patients undergoing coronary artery bypass grafting

Objectives: This study assessed the efficacy of oral consumption of N-acetyl cysteine (NAC) and melatonin (ML) in reducing early reperfusion injury and acute oxidative stress in patients undergoing coronary artery bypass grafting (CABG) with respect to the measurements of cardiac troponin I, lactate, malondealdehyde (MDA), and tumor necrosis factor-α (TNF-α) levels in the blood. Methods: This study was a randomized, open-label, placebo-controlled trial. Eighty eight patients, aged between 39 to 76 years and eligible for CABG, were recruited and randomly assigned into 3 intervention groups through a simple randomization method and underwent CABG surgery. Blood samples were withdrawn from arterial line, before the induction of anesthesia (before the start of surgery), after incision (before aortic cross-clamping), during global ischemia (during aortic cross-clamping), after aortic cross-clamping (on set of reperfusion), 15 minutes after reperfusion, and after recovery at the intense care unit. The blood samples were analyzed for troponin I, lactate, MDA and TNF-α levels. Results: There was no significant difference in influencing variables among the groups at the baseline. Overall mean troponin I, lactate, and TNF- α levels were significantly different between the intervention groups (all P < .001) at the recovery phase. Post-hoc pairwise comparisons showed that the differences of mean serum levels between ML and control groups were statistically significant for MDA, TNF- α, lactate, and troponin I (P < .001, P = .001, and P = .001, respectively). The differences between NAC and control groups and between ML and NAC groups were only significant for mean lactate level (P < .001 Conclusion: The current study revealed that ML and NAC are potent antioxidants with similar efficacy in terms of reducing CABG related cardiac injury and oxidative stress with the dosage employed for the interventio

Effects of N-acetyl cysteine and melatonin on early reperfusion injury in patients undergoing coronary artery bypass grafting: A randomized, open-labeled, placebo-controlled trial

OBJECTIVES: This study assessed the efficacy of oral consumption of N-acetyl cysteine (NAC) and melatonin (ML) in reducing early reperfusion injury and acute oxidative stress in patients undergoing coronary artery bypass grafting (CABG) with respect to the measurements of cardiac troponin I, lactate, malondealdehyde (MDA), and tumor necrosis factor-α (TNF-α) levels in the blood. METHODS: This study was a randomized, open-label, placebo-controlled trial. Eighty eight patients, aged between 39 to 76 years and eligible for CABG, were recruited and randomly assigned into 3 intervention groups through a simple randomization method and underwent CABG surgery. Blood samples were withdrawn from arterial line, before the induction of anesthesia (before the start of surgery), after incision (before aortic cross-clamping), during global ischemia (during aortic cross-clamping), after aortic cross-clamping (on set of reperfusion), 15 minutes after reperfusion, and after recovery at the intense care unit. The blood samples were analyzed for troponin I, lactate, MDA and TNF-α levels. RESULTS: There was no significant difference in influencing variables among the groups at the baseline. Overall mean troponin I, lactate, and TNF- α levels were significantly different between the intervention groups (all P < .001) at the recovery phase. Post-hoc pairwise comparisons showed that the differences of mean serum levels between ML and control groups were statistically significant for MDA, TNF- α, lactate, and troponin I (P < .001, P = .001, and P = .001, respectively). The differences between NAC and control groups and between ML and NAC groups were only significant for mean lactate level (P < .001). CONCLUSION: The current study revealed that ML and NAC are potent antioxidants with similar efficacy in terms of reducing CABG related cardiac injury and oxidative stress with the dosage employed for the intervention

Disparate Effects of Stilbenoid Polyphenols on Hypertrophic Cardiomyocytes In Vitro vs. in the Spontaneously Hypertensive Heart Failure Rat

Stilbenoids are bioactive polyphenols, and resveratrol (trans-3,5,40-trihydroxystilbene) is a representative stilbenoid that reportedly exerts cardioprotective actions. As resveratrol exhibits low oral bioavailability, we turned our attention to other stilbenoid compounds with a history of medicinal use and/or improved bioavailability. We determined the effects of gnetol (trans-3,5,20,60-tetrahydroxystilbene) and pterostilbene (trans-3,5-dimethoxy-40-hydroxystilbene) on cardiac hypertrophy. In vitro, gnetol and pterostilbene prevented endothelin-1-induced indicators of cardiomyocyte hypertrophy including cell enlargement and protein synthesis. Gnetol and pterostilbene stimulated AMP-activated protein kinase (AMPK), and inhibition of AMPK, using compound C or shRNA knockdown,abolished these anti-hypertrophiceffects. In contrast,resveratrol, gnetol, nor pterostilbene reduced blood pressure or hypertrophy in the spontaneously hypertensive heart failure (SHHF) rat. In fact, AMPK levels were similar between Sprague-Dawley and SHHF rats whether treated by stilbenoids or not. These data suggest that the anti-hypertrophic actions of resveratrol (and other stilbenoids?) do not extend to the SHHF rat, which models heart failure superimposed on hypertension. Notably, SHHF rat hearts exhibited prolonged isovolumic relaxationtime(an indicator of diastolicdys function),and this was improved by stilbenoid treatment.In conclusion, stilbenoid-based treatment as a viable strategy to prevent pathological cardiac hypertrophy,a major risk factor for heart failure,may be context-dependent and requires furtherstudy

Ginseng Berry Extract Rich in Phenolic Compounds Attenuates Oxidative Stress but not Cardiac Remodeling post Myocardial Infarction

The cardioprotective effects of ginseng root extracts have been reported. However, nothing is known about the myocardial actions of the phenolic compounds enriched in ginseng berry. Therefore, this study was undertaken to investigate the effects of American ginseng berry extract (GBE) in an experimental model of myocardial infarction (MI). Coronary artery ligation was performed on Sprague&#8315;Dawley male rats to induce MI after which animals were randomized into groups receiving either distilled water or GBE intragastrically for 8 weeks. Echocardiography and assays for malondialdehyde (MDA) and TNF-&#945; were conducted. Flow cytometry was used to test the effects of GBE on T cell phenotypes and cytokine production. Although GBE did not improve the cardiac functional parameters, it significantly attenuated oxidative stress in post-MI rat hearts. GBE treatment also resulted in lower than control levels of TNF-&#945; in post-MI rat hearts indicating a strong neutralizing effect of GBE on this cytokine. However, there was no effect of GBE on the proportion of different T cell subsets or ex-vivo cytokine production. Taken together, the present study demonstrates GBE reduces oxidative stress, however no effect on cardiac structure and function in post-MI rats. Moreover, reduction of TNF-&#945; levels below baseline raises concern regarding its use as prophylactic or preventive adjunct therapy in cardiovascular disease