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.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB et al. Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation 2012; 125: e2–e220.
World Health Organization Global Status Report On Noncommunicable Diseases 2010. World Health Organization: Geneva, 2011.
Artham SM, Lavie CJ, Milani RV, Patel DA, Verma A, Ventura HO . Clinical impact of left ventricular hypertrophy and implications for regression. Prog Cardiovasc Dis 2009; 52: 153–167.
Vital Statistics Public Use Data Files – 2011 Mortality Multiple Cause Files Centers for Disease Control and Prevention; 2008 [cited 9 July 2012]. Available from: http://www.cdc.gov/nchs/data/dvs/deaths_2009_release.pdf.
Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120: 1640–1645.
Gami AS, Witt BJ, Howard DE, Erwin PJ, Gami LA, Somers VK et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007; 49: 403–414.
Mottillo S, Filion KB, Genest J, Joseph L, Pilote L, Poirier P et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010; 56: 1113–1132.
Ervin RB . Prevalence of metabolic syndrome among adults 20 years of age and over, by sex, age, race and ethnicity, and body mass index: United States, 2003–2006. Natl Health Stat Report 2009; 1–7.
Peng N, Clark JT, Prasain J, Kim H, White CR, Wyss JM . Antihypertensive and cognitive effects of grape polyphenols in estrogen-depleted, female, spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 2005; 289: R771–R775.
Sivaprakasapillai B, Edirisinghe I, Randolph J, Steinberg F, Kappagoda T . Effect of grape seed extract on blood pressure in subjects with the metabolic syndrome. Metabolism 2009; 58: 1743–1746.
Feringa HH, Laskey DA, Dickson JE, Coleman CI . The effect of grape seed extract on cardiovascular risk markers: a meta-analysis of randomized controlled trials. J Am Diet Assoc 2011; 111: 1173–1181.
Negishi H, Xu JW, Ikeda K, Njelekela M, Nara Y, Yamori Y . Black and green tea polyphenols attenuate blood pressure increases in stroke-prone spontaneously hypertensive rats. J Nutr 2004; 134: 38–42.
Antonello M, Montemurro D, Bolognesi M, Di Pascoli M, Piva A, Grego F et al. Prevention of hypertension, cardiovascular damage and endothelial dysfunction with green tea extracts. Am J Hypertens 2007; 20: 1321–1328.
Nantz MP, Rowe CA, Bukowski JF, Percival SS . Standardized capsule of Camellia sinensis lowers cardiovascular risk factors in a randomized, double-blind, placebo-controlled study. Nutrition 2009; 25: 147–154.
Bogdanski P, Suliburska J, Szulinska M, Stepien M, Pupek-Musialik D, Jablecka A . Green tea extract reduces blood pressure, inflammatory biomarkers, and oxidative stress and improves parameters associated with insulin resistance in obese, hypertensive patients. Nutr Res 2012; 32: 421–427.
Nagao T, Hase T, Tokimitsu I . A green tea extract high in catechins reduces body fat and cardiovascular risks in humans. Obesity (Silver Spring) 2007; 15: 1473–1483.
Moraloglu O, Engin-Ustun Y, Tonguc E, Var T, Tapisiz OL, Ergun H et al. The effect of resveratrol on blood pressure in a rat model of preeclampsia. J Matern Fetal Neona 2012; 25: 845–848.
Bhatt SR, Lokhandwala MF, Banday AA . Resveratrol prevents endothelial nitric oxide synthase uncoupling and attenuates development of hypertension in spontaneously hypertensive rats. Eur J Pharmacol 2011; 667: 258–264.
Rivera L, Moron R, Zarzuelo A, Galisteo M . Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats. Biochem Pharmacol 2009; 77: 1053–1063.
Jalili T, Carlstrom J, Kim S, Freeman D, Jin H, Wu TC et al. Quercetin-supplemented diets lower blood pressure and attenuate cardiac hypertrophy in rats with aortic constriction. J Cardiovasc Pharmacol 2006; 47: 531–541.
Duarte J, Perez-Palencia R, Vargas F, Ocete MA, Perez-Vizcaino F, Zarzuelo A et al. Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats. Br J Pharmacol 2001; 133: 117–124.
Edwards RL, Lyon T, Litwin SE, Rabovsky A, Symons JD, Jalili T . Quercetin reduces blood pressure in hypertensive subjects. J Nutr 2007; 137: 2405–2411.
Egert S, Bosy-Westphal A, Seiberl J, Kurbitz C, Settler U, Plachta-Danielzik S et al. Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br J Nutr 2009; 102: 1065–1074.
Schulz KF, Altman DG, Moher D . CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. PLoS Med 2010 7: e1000251.
Larson A, Witman MA, Guo Y, Ives S, Richardson RS, Bruno RS et al. Acute, quercetin-induced reductions in blood pressure in hypertensive individuals are not secondary to lower plasma angiotensin-converting enzyme activity or endothelin-1: nitric oxide. Nutr Res 2012; 32: 557–564.
Chavanu K, Merkel J, Quan AM . Role of ambulatory blood pressure monitoring in the management of hypertension. Am J Health Syst Pharm 2008; 65: 209–218.
Babu PVA, Si H, Fu Z, Zhen W, Liu D . Genistein prevents hyperglycemia-induced monocyte adhesion to human aortic endothelial cells through preservation of the cAMP signaling pathway and ameliorates vascular inflammation in obese diabetic mice. J Nutr 2012; 142: 724–730.
Zeng G, Quon MJ . Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest 1996; 98: 894–898.
Kuboki K, Jiang ZY, Takahara N, Ha SW, Igarashi M, Yamauchi T et al. Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin. Circulation 2000; 101: 676–681.
Manach C, Williamson G, Morand C, Scalbert A, Remesy C . Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr 2005; 81: 230S–242S.
Ward NC, Croft KD, Puddey IB, Hodgson JM . Supplementation with grape seed polyphenols results in increased urinary excretion of 3-hydroxyphenylpropionic Acid, an important metabolite of proanthocyanidins in humans. J Agric Food Chem 2004; 52: 5545–5549.
Saura-Calixto F, Perez-Jimenez J, Tourino S, Serrano J, Fuguet E, Torres JL et al. Proanthocyanidin metabolites associated with dietary fibre from in vitro colonic fermentation and proanthocyanidin metabolites in human plasma. Mol Nutr Food Res 2010; 54: 939–946.
Rechner AR, Kuhnle G, Bremner P, Hubbard GP, Moore KP, Rice-Evans CA . The metabolic fate of dietary polyphenols in humans. Free Radic Biol Med 2002; 33: 220–235.
Rios LY, Gonthier MP, Remesy C, Mila I, Lapierre C, Lazarus SA et al. Chocolate intake increases urinary excretion of polyphenol-derived phenolic acids in healthy human subjects. Am J Clin Nutr 2003; 77: 912–918.
Deprez S, Brezillon C, Rabot S, Philippe C, Mila I, Lapierre C et al. Polymeric proanthocyanidins are catabolized by human colonic microflora into low-molecular-weight phenolic acids. J Nutr 2000; 130: 2733–2738.
Gu L, House SE, Rooney L, Prior RL . Sorghum bran in the diet dose dependently increased the excretion of catechins and microbial-derived phenolic acids in female rats. J Agric Food Chem 2007; 55: 5326–5334.
Piotrowska H, Kucinska M, Murias M . Biological activity of piceatannol: leaving the shadow of resveratrol. Mutat Res 2012; 750: 60–82.
Piver B, Fer M, Vitrac X, Merillon JM, Dreano Y, Berthou F et al. Involvement of cytochrome P450 1A2 in the biotransformation of trans-resveratrol in human liver microsomes. Biochem Pharmacol 2004; 68: 773–782.
Potter GA, Patterson LH, Wanogho E, Perry PJ, Butler PC, Ijaz T et al. The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYP1B1. Br J Cancer 2002; 86: 774–778.
Mullen W, Edwards CA, Crozier A . Absorption, excretion and metabolite profiling of methyl-, glucuronyl-, glucosyl- and sulpho-conjugates of quercetin in human plasma and urine after ingestion of onions. Br J Nutr 2006; 96: 107–116.
Perez A, Gonzalez-Manzano S, Jimenez R, Perez-Abud R, Haro JM, Osuna A et al. The flavonoid quercetin induces acute vasodilator effects in healthy volunteers: correlation with beta-glucuronidase activity. Pharmacol Res 2014; 89: 11–18.
Terao J, Murota K, Kawai Y . Conjugated quercetin glucuronides as bioactive metabolites and precursors of aglycone in vivo. Food Funct 2011; 2: 11–17.
Erlund I, Kosonen T, Alfthan G, Maenpaa J, Perttunen K, Kenraali J et al. Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers. Eur J Clin Pharmacol 2000; 56: 545–553.
Bosse JD, Lin HY, Sloan C, Zhang QJ, Abel ED, Pereira TJ et al. A low-carbohydrate/high-fat diet reduces blood pressure in spontaneously hypertensive rats without deleterious changes in insulin resistance. Am J Physiol Heart Circ Physiol 2013; 304: H1733–H1742.
Barona J, Aristizabal JC, Blesso CN, Volek JS, Fernandez ML . Grape polyphenols reduce blood pressure and increase flow-mediated vasodilation in men with metabolic syndrome. J Nutr 2012; 142: 1626–1632.
Webb AJ, Patel N, Loukogeorgakis S, Okorie M, Aboud Z, Misra S et al. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension 2008; 51: 784–790.
Kapil V, Milsom AB, Okorie M, Maleki-Toyserkani S, Akram F, Rehman F et al. Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO. Hypertension 2010; 56: 274–281.
Goncalves FM, Jacob-Ferreira AL, Gomes VA, Casella-Filho A, Chagas AC, Marcaccini AM et al. Increased circulating levels of matrix metalloproteinase (MMP)-8, MMP-9, and pro-inflammatory markers in patients with metabolic syndrome. Clin Chim Acta 2009; 403: 173–177.
Heger A, Ferk F, Nersesyan A, Szekeres T, Kundi M, Wagner KH et al. Intake of a resveratrol-containing dietary supplement has no impact on DNA stability in healthy subjects. Mutat Res 2012; 749: 82–86.
Bo S, Ciccone G, Castiglione A, Gambino R, De Michieli F, Villois P et al. Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial. Curr Med Chem 2013; 20: 1323–1331.
Egert S, Boesch-Saadatmandi C, Wolffram S, Rimbach G, Muller MJ . Serum lipid and blood pressure responses to quercetin vary in overweight patients by apolipoprotein E genotype. J Nutr 2010; 140: 278–284.
Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab 2011; 14: 612–622.
Bhatt JK, Thomas S, Nanjan MJ . Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr Res 2012; 32: 537–541.
Crandall JP, Oram V, Trandafirescu G, Reid M, Kishore P, Hawkins M et al. Pilot study of resveratrol in older adults with impaired glucose tolerance. J Gerontol A Biol Sci Med Sci 2012; 67: 1307–1312.
Fujitaka K, Otani H, Jo F, Jo H, Nomura E, Iwasaki M et al. Modified resveratrol Longevinex improves endothelial function in adults with metabolic syndrome receiving standard treatment. Nutr Res 2011; 31: 842–847.
Fukino Y, Ikeda A, Maruyama K, Aoki N, Okubo T, Iso H . Randomized controlled trial for an effect of green tea-extract powder supplementation on glucose abnormalities. Eur J Clin Nutr 2008; 62: 953–960.
Brown AL, Lane J, Holyoak C, Nicol B, Mayes AE, Dadd T . Health effects of green tea catechins in overweight and obese men: a randomised controlled cross-over trial. Br J Nutr 2011; 106: 1880–1889.
Feng Z, Wei RB, Hong Q, Cui SY, Chen XM . Grape seed extract enhances eNOS expression and NO production through regulating calcium-mediated AKT phosphorylation in H2O2-treated endothelium. Cell Biol Int 2010; 34: 1055–1061.
Liu X, Qiu J, Zhao S, You B, Ji X, Wang Y et al. Grape seed proanthocyanidin extract alleviates ouabain-induced vascular remodeling through regulation of endothelial function. Mol Med Report 2012; 6: 949–954.
Bailey RL, Gahche JJ, Miller PE, Thomas PR, Dwyer JT . Why US adults use dietary supplements. JAMA Intern Med 2013; 173: 355–361.
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42: 1206–1252.
Greenberg J . Are blood pressure predictors of cardiovascular disease mortality different for prehypertensives than for hypertensives? Am J Hypertens 2006; 19: 454–461.
Taylor BC, Wilt TJ, Welch HG . Impact of diastolic and systolic blood pressure on mortality: implications for the definition of "normal". J Gen Intern Med 2011; 26: 685–690.
We acknowledge Maureen Murtaugh, PhD, RD, for providing statistical consultation. This study was funded by a grant from Melaleuca, Inc., and by the University of Utah College of Health Research Incentive grant.
TJ received research funding from Melaleuca, Inc. for this study. ABR is an employee of Melaleuca, Inc. Other authors do not declare any conflict of interest.
About this article
Cite this article
Biesinger, S., Michaels, H., Quadros, A. et al. A combination of isolated phytochemicals and botanical extracts lowers diastolic blood pressure in a randomized controlled trial of hypertensive subjects. Eur J Clin Nutr 70, 10–16 (2016). https://doi.org/10.1038/ejcn.2015.88
Dietary phytochemical index associated with cardiovascular risk factor in patients with type 1 diabetes mellitus
BMC Cardiovascular Disorders (2021)
The effects of resveratrol on lipid profiles and liver enzymes in patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials
Lipids in Health and Disease (2020)
The Effects of Resveratrol Supplementation on Endothelial Function and Blood Pressures Among Patients with Metabolic Syndrome and Related Disorders: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
High Blood Pressure & Cardiovascular Prevention (2019)
Metabolites of flavonoid compounds preserve indices of endothelial cell nitric oxide bioavailability under glucotoxic conditions
Nutrition & Diabetes (2017)
npj Precision Oncology (2017)