Vitis vinifera / Wijnstok

Grape Juice, Purple

Scientific Name(s): Vitis vinifera L., V. labrusca L., V. rotundifolia Michx. Family: Vitaceae
Common Name(s): European or “Old World” grapes (most common; 95% of grapes) ( V. vinifera ); American bunch grapes ( V. labrusca ); muscadine grapes 

Grapes grow in bunches (from 6 to 300) on woody, climbing vines. These fruits come in a variety of colors, including black, blue, golden, green, red, white, and purple. Certain flavonoids present in the purple grape varieties possess beneficial actions not seen in the others (see Wine monograph). V. vinifera is a deciduous climber with several stems, tendrils, clusters of pale, green flowers, and palm-shaped leaves. In addition to the kinds of grapes listed above, French hybrid varieties of grapes exist that were developed mainly for wine making. Grapes are native to southern Europe and western Asia but are cultivated in warm temperate regions throughout the world. 1 , 2 Grape juice is the fluid expressed from ripened grapes. They are passed through a separator, which removes the skins, stems, seeds, and pulp. The juice then is treated and pasteurized. 1

Grape leaves have been seen in fossils dating back to prehistoric times. Grapes were domesticated in western Asia before 5000 BC and have been mentioned in biblical writings and depicted in tomb paintings dating back to 2375 BC. Circa 1635, Jesuit fathers brought Spanish grapes to Mexico, establishing vineyards in what is now Socorro, New Mexico, the area of the earliest planting of grapes in the United States. 1 In 1652, Nicholas Culpeper recommended grapes as a mouthwash. 2 In the 1850s, California became involved in grape culture. 1 In 1927, physician A.M. Liebstein mentioned grapes as being beneficial for dyspeptic and febrile conditions, liver and kidney ailments, tuberculosis, hemorrhoids, varicose veins, osteomyelitis, gangrene, and cancer. The Grape Cure (1928, Johanna Brandt) claimed that grapes had cured the author's abdominal cancer. 3 Modern scientific studies demonstrate a variety of beneficial effects from grapes.

Grapes are ≈ 80% water and contain 70 calories/100 g. The sugar (carbohydrate) content is ≈ 16%. 1 Commercial grape juice is lower in sucrose than other fruit juices. 4 Other sugars, amino acids, and organic acids in grape juice and wines have been detected. 5 The amino acid arginine has been separated from grape juice. 6 Grapes contain tartaric and carboxylic acids, including malic, citric, lactic, succinic, and shikimic acids. 2 , 7 Vitamins A, B 1 , B 2 , and C also are present in grapes, as are minerals including chromium and potassium. 1 , 2 Anthocyanins are found in grapes with red pigments, 2 as well as in other pigmented fruits such as the blackberry, strawberry, and blueberry. 8 A review discussing anthocyanins in grapes, juices, and wines is available. 9 Flavonoids including quercetin, catechins, myricetin, and kaempferol are the more important constituents in purple grape juice and red wine.10 Catechin concentrations are substantial in red wine (27 to 96 mg/L) but low to negligible in white wine and commercially available grape juices tested in another report. 11 Other constituents found in grapes include tannins, inositol, choline, and pectin. 2 Glutathione and thiol-containing compounds have been found in the juice. 12 Isomers of resveratrol in grape juice and wine also are present, 13 as are antioxidants. 14

Grape Juice, Purple Uses and Pharmacology
In general, grapes are nourishing and mildly laxative, offering support in the GI tract and liver. Red grape leaves are known to be astringent and anti-inflammatory. Red leaves and grapes are used in the treatment of varicose veins, hemorrhoids, and capillary fragility. 2 Grape juice is high in chromium, a mineral that is part of the glucose tolerance factor, which works with insulin to promote utilization of sugar. 1

Cardiovascular function
Attention has focused on purple grape juice and its beneficial effects in heart health. Certain flavonoids in purple grape juice and red wines may be responsible for keeping heart-damaging blood clots from forming. Aspirin is used for this purpose as well, but its effects against platelet aggregation are negated by adrenaline, which is released under stressful situations. Flavonoids are not affected by adrenaline, and thus are still available to prevent clot formation.15

Pure grape juice's ability to slow onset of oxidation, reduce platelet activity, and increase nitric oxide production collectively may contribute to healthy cardiovascular function. 16

Animal data
Research reveals no animal data in regards to the use of purple grape juice for cardiovascular activity.

Clinical data
An older report demonstrates anti-platelet aggregation and thrombin production to be reduced by grape juice and red wine. However, the study suggests that the ethanol contained in the wine is the dominant anti-aggregatory component because of its greater ability to prevent platelet aggregation as compared with grape juice. 17 In a randomized, crossover study involving 10 patients, purple grape juice consumption for 1 week reduced the whole blood platelet aggregation response by 77% vs orange and grapefruit juices, confirming purple grape juice's effects in decreasing risk of coronary thrombosis and MI because of increased polyphenolic concentration present (≈ 3 times more than the other juices). 17 Another report in 15 coronary artery disease (CAD) patients concluded that short-term ingestion of purple grape juice improved endothelium-dependent vasodilation and prevented LDL oxidation, reducing negative cardiovascular outcomes. This was shown to be caused by flavonoid components present. 10 Compared with controls, 14 patients with CAD, consuming 7 to 10 mL/kg/day of purple grape juice for 14 days, demonstrated increased lag time measurements, which determine cholesterol oxidation time. (The longer the lag time, the slower the onset of oxidation.) It was concluded that this delay in oxidation of LDL cholesterol is beneficial because it is usually a key contributor to the development of atherosclerosis.Other uses

Grape juice possesses marked antiviral properties in vitro against such viruses as poliovirus and herpes simplex virus. Tannins may be responsible for these effects. Studies also have demonstrated grape juice as being antibacterial, drastically reducing tooth decay in animals. The caffeic acid constituent prevents cancer in animals. Raisins are linked to lower rates of cancer deaths in elderly patients. 3

There is no clinical evidence to support specific dosage recommendations for purple grape juice.

Generally recognized as safe or used as food. Avoid dosages above those found in food because safety and efficacy are unproven.

None well documented.

Adverse Reactions
Research reveals little or no information regarding adverse reactions with the use of purple grape juice.

Research reveals little or no information regarding toxicology with the use of purple grape juice.

1. Ensminger A, et al. Foods & Nutrition Encyclopedia, 2nd ed. (Vol.1). Boca Raton, FL: CRC Press;1994:1093-99.
2. Chevallier A. The Encyclopedia of Medicinal Plants . New York, NY: DK Publishing;1996:281.
3. Carper J. The Food Pharmacy . New York, NY: Bantam Books;1988:211-12.
4. Yoon J, et al. Chemometric aspects of sugar profiles in fruit juices using HPLC and GC. Bull Korean Chem Soc 1997;18(7):695-702.
5. Linget C, et al. Online dialysis with HPLC for the automated preparation and analysis of amino acids, sugars, and organic acids in grape juice and wines. Analusius 1998;26(1):35-39.
6. Austin K, et al. Spectrophotometric assay for arginine in grape juice and must. Am J Enol Vitic 2000;51(3):227-232.
7. Fuleki T, et al. Carboxylic acid composition of authentic varietal and commercial grape juice. J AOAC Int 1993;76(3):591-600.
8. Koswig S, et al. HPLC method for determination of anthocyanins in colored juices and other pigmented foods. Fluess Obst 1995;62(4):125,128-30.
9. Mazza G. Anthocyanins in grapes and grape products. Crit Rev Food Sci Nutr 1995;35(4):341-71.
10. Stein J, et al. Purple grape juice improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease. Circulation 1999;100(10):1050-55.
11. Arts I, et al. Catechin contents of foods commonly consumed in the Netherlands. Part 2. Tea, wine, fruit juices, and chocolate milk. J Agric Food Chem 2000;48(5):1752-57.
12. Park S, et al. Automated HPLC analysis of glutathione and thiol-containing compounds in grape juice and wine using pre-column derivatization with fluorescence detection. Food Chem 2000;68(4):475-80.
13. Soleas G, et al. A derivatized gas chromatographic-mass spectrometric method for the analysis of both isomers of resveratrol in juice and wine. Am J Enol Vitic 1995;46(3):346-52.
14. Wang H, et al. Total antioxidant capacity of fruits. J Agric Food Chem 1996;44(3):701-05.
15. . .
17. Pace-Asciak C, et al. Wines and grape juices as modulators of platelet aggregation in healthy human subjects. Clin Chim Acta 1996;246(1,2):163-82.
18. Keevil J, et al. Grape juice, but not orange juice or grapefruit juice, inhibits human platelet aggregation. J Nutr 2000;130(1):53-56.

Andere links naar Vitis

Biological activity of procyanidins from Vitis vinifera LE Bombardelli, P Morazzoni, M Carini, G Aldini… - BioFactors, 1997 - IOS Press
... Page 3. E. Bombardelli et al. / Biological activity of procyanidins from Vitis vinifera L. 431 ...References [1] Oxidative stress, in: Lipoproteins and Cardiovascular Dysfunction, C. Rice-Evans and KR Bruckdorfer, eds, Portland Press Research Monograph, London, UK, 1995. ...

Vitis vinifera in de gemmotherapie

De Wijnstok is sinds lang gekend om zijn vrucht en alle bijproducten die eruit voortvloeien. Minder gekend is het gebruik van zijn blaadjes, zijn sap (als oogwater) en zijn knoppen. Zijn werking in gemmotherapie ligt bij chronische ontstekingen op alle niveaus.
  • Op niveau van de huid vormt de Wijnstokknop een remedie voor bepaalde huidaandoeningen, roos, wratten en collagenose. De meeste symptomen hebben een inwendige oorsprong, dikwijls intestinaal.
  • Op gebied van het spijsverteringsstelsel werkt deze knop bij intestinale ontstekingen, zoals granulomateuze rectocolitis, colitis, Crohn ileïtis.
  • Als anti-inflammatoire ageert de Wijnstokknop op het veneuze vaatstelsel: bij aambeien, pijnlijke flebitis, baarmoederbloedingen, bij de menopauze, pijnlijke overvloedige maandstonden (hypermenorrhea), adenitis ( lymfeklieren ontsteking).
  • Het is vooral op de gewrichten dat de anti-inflammatoire eigenschappen van de Wijnstokknop vooral toepassing vinden, en meeste bij chronische aandoeningen zoals acute gewrichtsreuma, verschillende artrosepijnen, coxartrose, gonartrose, vooral deze van de kleine gewrichten.

Vitis vinifera

La vigne rouge est reconnue pour ses capacités à traiter le syndrome des jambes lourdes et d'autres troubles circulatoires ou veineux, tels que les varices et les hémorroïdes. Elle est aussi très efficace pour traiter les migraines et les règles douloureuses.

Vigne rougeNom scientifique : Vitis vinifera
Noms communs : vigne rouge, vigne à vin, vigne vinifère, vigne des teinturiers
Nom anglais: grape vine

Formes et préparations : gélules, décoctions, infusions, baumes, lotions, teinture mère

Propriétés médicinales de la vigne rouge

Traitement des problèmes de circulation sanguine (syndrome des jambes lourdes, varices, hémorroïdes) et des règles douloureuses ou irrégulières.

En baume et en lotion, la vigne rouge est recommandée pour lutter contre les varices et les jambes lourdes. En décoction et en infusion, elle régule l' insuffisance veineuse et les règles abondantes.

Anti-inflammatoire et antioedémateuse : jambes lourdes, fragilité capillaire (petits vaisseaux situés sous la peau), hémorroïdes, varices ; action antioxydante ; propriétés diurétiques.

La vigne rouge renforce l'organisme dans les cas de troubles digestifs ou hépatiques. Elle permet l'évacuation des mucosités bronchiques et offre ses propriétés apaisantes à la peau.

La vigne rouge est un arbrisseau sarmenteux à tiges grimpantes. Cultivée en Europe depuis l'Antiquité, essentiellement pour ses fruits, elle a été, par la suite, introduite dans le monde entier. Ses feuilles sont palmées et son fruit, le raisin, est utilisé pour produire le vin. Une variété de vigne rouge, la Vitis vinifera sylvestris , est une espèce rare et protégée, dont la récolte est strictement interdite en France.

Les phytothérapeutes utilisent les feuilles, les fruits (le raisin) ainsi que la sève et les pépins des raisins.

La vigne rouge contient des polyphénols (notamment du resvératrol) et des flavonoïdes (oligo-proanthocyanidines et quercétine). Ce sont ces éléments qui lui confèrent ses propriétés antioxydantes et vasoconstrictrices.

Utilisation et posologie de la vigne rouge

Pour traiter l'insuffisance veineuse et les varices : prendre quotidiennement, en décoction ou en infusion, de 30 à 50 g d'extrait de feuilles de vigne ou de 15 à 30 g d'extrait de pépins.
Précautions d'emploi de la vigne rouge
La vigne rouge contenant des tanins astringents (agissant notamment au niveau de l'utérus), est déconseillée, à fortes doses, aux femmes enceintes et aux jeunes enfants.

Pas de contre-indications connues.

En association avec d'autres plantes (l'hamamélis, notamment), son action sur la circulation sanguine en général et sur les varices en particulier est renforcée (baume avec de l'aubépine, du cyprès et du chardon-Marie ).

Il est déconseillé de consommer des doses trop importantes de vigne rouge lors de la prise d'anticoagulants, car elle pourrait réduire leur efficacité.

Phytother Res. 2009 Sep;23(9):1197-204. doi: 10.1002/ptr.2761.
Review of the pharmacological effects of Vitis vinifera (Grape) and its bioactive compounds.
Nassiri-Asl M1, Hosseinzadeh H.

Vitis vinifera, known as the grapevine, is native to southern Europe and Western Asia. Grape seed and skin contain several active components including flavonoids, polyphenols, anthocyanins, proanthocyanidins, procyanidines, and the stilbene derivative resveratrol. Grape seed extract in particular has been reported to possess a broad spectrum of pharmacological and therapeutic effects such as antioxidative, anti-inflammatory, and antimicrobial activities, as well as having cardioprotective, hepatoprotective, and neuroprotective effects. Thus, the present review attempts to give a short overview on the pharmacological, toxicological, and clinical studies of grape and its active components.

Nutr Res. 2008 Nov;28(11):729-37. doi: 10.1016/j.nutres.2008.08.007.
Cardioprotective actions of grape polyphenols.
Leifert WR1, Abeywardena MY.
The aim of this review is to discuss the accumulating evidence that suggests that grape extracts and purified grape polyphenols possess a diverse array of biological actions and may be beneficial in the prevention of some inflammatory-mediated diseases including cardiovascular disease. The active components from grape extracts, which include the grape seed, grape skin, and grape juice, that have been identified thus far include polyphenols such as resveratrol, phenolic acids, anthocyanins, and flavonoids. All possess potent antioxidant properties and have been shown to decrease low-density lipoprotein-cholesterol oxidation and platelet aggregation. These compounds also possess a range of additional cardioprotective and vasoprotective properties including antiatherosclerotic, antiarrhythmic, and vasorelaxation actions. Although not exclusive, antioxidant properties of grape polyphenols are likely to be central to their mechanism(s) of action, which also include cellular signaling mechanisms and interactions at the genomic level. This review discusses some of the evidence favoring the consumption of grape extracts rich in polyphenols in the prevention of cardiovascular disease. Consumption of grape and grape extracts and/or grape products such as red wine may be beneficial in preventing the development of chronic degenerative diseases such as cardiovascular disease.

World J Mens Health. 2015 Aug;33(2):109-16. doi: 10.5534/wjmh.2015.33.2.109. Epub 2015 Aug 19.
The Effect of Vitis vinifera L. Juice on Serum Levels of Inhibin B, Sperm Count in Adult Male Rats.
Afzalzadeh MR1, Ahangarpour A2, Amirzargar A3, Varnamkhasti MK1, Ganjalidarani H1.
Vitis vinifera is a species of Vitis that is native to the Mediterranean region, central Europe, and southwestern Asia, and has been used as a drug in traditional medicine. Traditional medicinal plants have been used for medical purposes with increasing effectiveness. It is important to identify drugs that inhibit spermatogenesis. Therefore, the present study aimed to investigate the effect of grape juice (GJ) on serum levels of inhibin B and sperm count in normal male rats.
Thirty-five adult male rats were randomly divided into five groups, each containing seven rats. Rats in the control group received 1 mL of normal saline over the course of the study. The experimental groups received GJ (100, 200, 400, and 1,600 mg/kg, orally, for 35 days consecutively). At the end of the treatment period, fertility indices were measured, including body weight difference, sex organ weight, sperm motility and count, epididymal sperm reserve, daily sperm production (DSP), and serum inhibin B levels.
We found that GJ reduces body weight difference, was associated with decreased sperm motility and count in all treatment groups (p≤0.05 and p≤0.001, respectively). Moreover, DSP was significantly decreased in all treatment groups compared to the control group (p≤0.05), except in the group receiving 100 mg/kg of GJ. Inhibin B levels were significantly decreased in all treatment groups (p≤0.05).
The results of our study suggest that GJ in all doses, but especially in higher doses, may decrease fertility in male rats.

Grapes and Cardiovascular Disease1–3
Mustali M. Dohadwala and Joseph A. Vita *
+ Author Affiliations
Evans Department of Medicine and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118

Epidemiological studies suggest that consumption of wine, grape products, and other foods containing polyphenols is associated with decreased risk for cardiovascular disease. The benefits of wine consumption appear to be greater than other alcoholic beverages. Experimental studies indicate that grape polyphenols could reduce atherosclerosis by a number of mechanisms, including inhibition of oxidation of LDL and other favorable effects on cellular redox state, improvement of endothelial function, lowering blood pressure, inhibition of platelet aggregation, reducing inflammation, and activating novel proteins that prevent cell senescence, e.g. Sirtuin 1. Translational studies in humans support these beneficial effects. More clinical studies are needed to confirm these effects and formulate dietary guidelines. The available data, however, strongly support the recommendation that a diet rich in fruits and vegetables, including grapes, can decrease the risk for cardiovascular disease.

The medicinal value of the grapevine and its fruit, Vitis vinifera, has been recognized for over 6000 y (1). In ancient Egypt, sap from grapevines was made into an ointment to treat skin and eye conditions. The fruit was crushed into wine elixirs or ripened to serve as therapeutics for a multitude of conditions, including nausea, constipation, cholera, smallpox, liver disease, and cancers. In the past century, disease states such as hypertension, coronary heart disease, and stroke have become markedly more prevalent. Despite aggressive management of cardiovascular risk factors and improved outcomes, the societal burden from cardiovascular disease remains high, and in the past few decades there has been increased interest in lifestyle and dietary approaches to reducing cardiovascular risk. Recent evidence suggests there are cardioprotective benefits from diets rich in natural fruits and vegetables, such as grapes. This review will outline the epidemiological evidence supporting the cardiovascular benefits of grape consumption. We will then consider experimental and translational studies that elucidate potential mechanisms of benefit.

The “French Paradox.”
In 1979, St. Leger et al. (2) drew attention to the protective effects of wine against ischemic heart disease. Epidemiologic data collected by the WHO revealed a discord in cardiovascular mortality in a cohort of subjects from Toulouse, France, compared with other cohorts from 17 Western countries, including the United States and the United Kingdom (3–5). Interestingly, the French cohort had lower risk despite higher consumption of saturated fat (3). This counterintuitive finding, which was coined the “French Paradox,” stimulated further analysis leading to the suggestion that increased consumption of wine in France and other Mediterranean countries might be the explanation.

More recent epidemiological studies provide further support for a beneficial effect of wine. Initially, reduced risk was attributed to its ethanol content (3,6–8). Other studies, however, indicated that wine might confer benefits above and beyond those of other alcoholic beverages, suggesting that nonalcoholic factors in wine may also play a protective role (9–11). For example, wine consumption was found to be cardioprotective, whereas beer intake was not, in a meta-analysis of 13 studies and 209,418 participants (9). Despite these data, it remains possible that ethanol and/or other aspects of the Mediterranean diet or lifestyle might better explain the French paradox.

Grape polyphenols and cardiovascular risk.
Grapes contain a wide variety of polyphenol compounds, including flavonoids, phenolic acids, and resveratrol. There is extensive epidemiological evidence suggesting that dietary intake of these compounds reduces cardiovascular mortality (12–17). Numerous studies in vitro as well as in animals and humans demonstrate beneficial effects of grape polyphenols on traditional cardiovascular risk factors (Table 1). Population-based studies have observed markedly lower cardiovascular disease mortality in cohorts with higher consumption of relevant flavonoids, including flavonols, flavones, and flavan-3-ols (13–15,18–20). In a study of 34,489 postmenopausal American women, dietary intake of foods containing flavanones and anthocyanidins was associated with decreased cardiovascular and all-cause mortality (21). In that study, consumption of red wine was specifically associated with decreased risk of coronary heart disease.

Further evidence that polyphenol content in wine accounts for cardiovascular benefits may be derived from studies comparing different types of wine. The highest concentrations of grape polyphenols are found in the skin, stems, and seeds. The longer contact with these components during the production of red wine increases polyphenolic content up to 10-fold compared with white wine (22). Investigators suggest that this difference in phytochemical content explains the reported additional health benefit of red wine over white wine or grape juice (23). In support of this possibility, numerous human studies suggest that red wine has greater antioxidant effects and more favorable effects on lipid metabolism than white wine (24). It must be acknowledged, however, that several observational studies from North American cohorts did not reveal differential effects of red and white wines (10,25).

Negative studies of polyphenol consumption and cardiovascular disease.
Despite the large body of evidence supporting a link between polyphenol consumption and reduced cardiovascular risk, some concerns are worth noting. A number of well-done observational studies have shown no relationship between polyphenol consumption and cardiovascular outcomes (26,27). These apparently discrepant results might be explained by a variety of factors. Dietary questionnaires are an imperfect method to assess polyphenol intake and the available studies have focused on only a few specific compounds. In addition, the overall levels and ranges of polyphenol intake within the studied cohorts and the confounding effects of socioeconomic class, other dietary factors, and concomitant risk factors might explain the lack of consistent findings (28). Despite these lingering questions, the accumulated data from multiple studies prompted the AHA to recommend a diet rich in fruits and vegetables, including grapes, as an approach to prevent cardiovascular disease (29).

Mechanistic studies
Antioxidant properties.
Grape polyphenols have important antioxidant properties. According to the oxidative hypothesis, oxidative modification of LDL is a primary initiating event in atherosclerosis [reviewed by Diaz et al. (30)]. As a corollary, this hypothesis suggests that antioxidant treatment to limit LDL oxidation should prevent atherosclerosis and its complications. These concepts stimulated many studies that examined the antiatherosclerotic effects of antioxidant vitamins in animal models and surrogate endpoints in humans and ultimately prompted investigators to conduct large-scale clinical trials of antioxidant treatment for cardiovascular disease (31). Despite the failure of randomized trials with antioxidant vitamins, such as vitamin E, vitamin C, and β carotene, there remains strong evidence that an imbalance between production of reactive oxygen species and antioxidant defense mechanisms contributes to the pathogenesis of atherosclerosis (32). We now understand that redox signaling is important for normal cellular physiology and the response to environmental stress, possibly explaining why high-dose antioxidant supplementation does not show benefits. It remains clear, however, that “oxidative stress” has pathophysiological effects on enzyme function, cell signaling, and gene expression that contribute to disease development. Interventions that affect cellular redox status have the potential to reduce risk.

In this context, many studies investigating beneficial mechanisms of grape polyphenols have focused on their antioxidant properties. Flavonoids and other polyphenols found in grapes have the capacity to scavenge reactive oxygen species (33). When fed to animals and humans, such compounds have been shown to increase the radical scavenging capacity of plasma (34). In addition to scavenging radicals, polyphenols alter cellular redox status by other mechanisms, including chelating metals that promote lipid peroxidation and modulating the activity of antioxidant enzymes.

Given the oxidative hypothesis of atherosclerosis, a potentially important property of grape-derived polyphenols is the ability to inhibit LDL oxidation. In the key initial step in atherogenesis, oxidized LDL (oxLDL) is taken up by macrophages in an unregulated manner to form foam cells. OxLDL also promotes atherosclerosis by altering endothelial function, stimulating platelet activation, and inducing a proinflammatory state in the vascular wall (30). In vitro studies have demonstrated that grape-derived flavonoids and resveratrol limit ex vivo LDL oxidation (35). Red wine has been found to be more potent than white wine or pure ethanol in this regard (36).

There is evidence that these effects are relevant to atherogenesis in animals. Hayek et al. (37) observed that hypercholesterolemic mice consuming wine polyphenols for 6 wk had markedly less atherosclerosis than control animals. These treatments were associated with protection against LDL oxidation. Vinson et al. (38) demonstrated reduced aortic atherosclerosis in hamsters supplemented with polyphenol-rich beverages. Zern et al. (39) observed a reduction in cholesterol accumulation in the aortas of ovariectomized guinea pigs fed a lyophilized grape preparation. Interestingly, Stocker et al. (40) observed reduced atherosclerosis but no decrease in LDL oxidation within the arterial wall following treatment with dealcoholized red wine in mice, suggesting that mechanisms other than LDL protection may also be important.

To translate these mechanistic findings to humans, Stein et al. (41) demonstrated a reduction in the susceptibility of LDL to copper-mediated oxidation following consumption of purple grape juice for 2 wk in patients with coronary artery disease. Red wine consumption in healthy subjects also reduced urinary levels of prostoglandin F2-α, a marker of systemic lipid peroxidation (42). A similar effect on urinary isoprostane concentrations were observed in pre- and postmenopausal women following treatment with lyophilized grape powder for 4 wk (43). At the present time, no study, to our knowledge, has shown a relation between polyphenol consumption and reduced atherosclerosis in humans. It remains to be determined whether inhibition of LDL oxidation is a clinically relevant mechanism in humans.

Endothelial function.
The vascular endothelium plays a central role in the regulation of vascular tone, thrombosis, local inflammation, and cell proliferation by producing paracrine factors that act on the arterial wall and blood cells (44). Endothelium-derived nitric oxide (NO) is a vasodilator and inhibits platelets, leukocyte adhesion to the endothelial surface, and proliferation of vascular smooth muscle cells. When healthy, the endothelium promotes a vasodilator, antithrombotic, and antiinflammatory state. However, cardiovascular disease risk factors alter endothelial phenotype in a manner that promotes atherogenesis, lesion progression, and plaque vulnerability.

In humans, endothelial dysfunction is associated with traditional risk factors and established atherosclerosis (45). Furthermore, endothelial dysfunction predicts progression of atherosclerosis and incidence of cardiovascular events (46,47). Furthermore, endothelial dysfunction is reversed by a number of interventions proven to reduce cardiovascular risk, such as lipid-lowering therapy, angiotensin-converting inhibitors, smoking cessation, and weight loss (44). Failure of the endothelium to respond to such therapy identifies patients at higher risk (48).

In vitro studies have demonstrated favorable effects of grape products on endothelial function. In cultured endothelial cells, wine, grape juice, grape seed extract, and specific polyphenols increase the activity of the endothelial isoform of NO synthase and stimulate NO production (49,50). In the short term, polyphenols stimulate endothelial NO synthase phosphorylation via phsophatidylinositol-3-hydroxy kinase and Akt (51). Longer term exposure to red wine extracts or resveratrol stimulates an increase in enzyme expression and activity (49,50). The effects of resveratrol on endothelial function may be mediated through an effect on Sirtuin-1, which regulates the expression of genes related to cell survival and the stress response (6,52). Furthermore, activation of Sirtuin-1 decreases the activity of p53, a regulator of apoptosis and the cell cycle, and activates AMP-dependent protein kinase, a regulator of cellular energy status (53).

Human studies support a benefit of grape beverages on endothelial function (54). Stein et al. (41) observed that consumption of purple grape juice for 2 or 4 wk improved endothelium-dependent brachial artery flow-mediated dilation in patients with coronary artery disease. Dealcoholized wine also improved brachial artery flow-mediated dilation in healthy subjects (55). Interestingly, red wine consumption prevents the acute impairment of endothelial function that occurs following cigarette smoking (56) or consumption of a high-fat meal (57).

In addition to the effects on NO, grapes have important effects on other molecular aspects of vascular function. For example, flavonoid-containing beverages increase endothelial production of prostacyclin and suppress production of endothelin-1, a potent endothelium-derived vasoconstrictor (58,59). In regard to regulation of fibrinolysis, catechins and resveratrol increase protein levels and activity of tissue plasminogen activator, an effect that is likely to be cardioprotective (60). Finally, there is increasing evidence that polyphenols affect endothelial regulation of inflammation. Red wine constituents reduce adhesion of monocytes to the endothelial surface and block cytokine-induced expression of endothelial adhesion molecules (61). Thus, grape polyphenols induce multiple favorable changes in endothelial cell phenotype that could reduce cardiovascular risk.

Antiplatelet effects.
Platelets play a critical role in all phases of atherosclerosis. Antiplatelet drugs, particularly aspirin, have proven beneficial effects on cardiovascular risk. Because polyphenols have been shown to have platelet inhibitory effects, there is great interest in the possibility that grape consumption might provide similar protection. In vitro studies have shown that grape-derived polyphenols inhibit platelet activity and elucidated a number of potential mechanisms. Flavonoids inhibit cyclooxygenase and reduce production of thromboxane A2. Red wine polyphenols also decrease platelet production of hydrogen peroxide and inhibit activation of phospholipase C and protein kinase C (62). Dilute grape juice inhibits platelet aggregation and this effect is associated with decreased production of superoxide anion and increased platelet NO production (34).

Feeding grape juice to animals also has important antiplatelet effects. Demrow et al. (63) used a coronary artery platelet aggregation model (Folts model) that mimics acute coronary syndromes to demonstrate platelet inhibition following oral administration of red wine to dogs. Similar effects were observed in monkeys (64) and these effects have been shown to depend on NO production (65).

Human studies have also demonstrated antiplatelet effects of grape-derived beverages. Freedman et al. (34) demonstrated that grape juice consumption for 14 d decreased platelet aggregation and superoxide production and increased NO production in healthy volunteers. In that study, grape juice also inhibited protein kinase C and spared cellular antioxidants. Red wine has more potent antiplatelet effects than white wine (66) and these effects are not seen with other beverages, such as orange juice and grapefruit juice, which contain other antioxidants (67).

Antiinflammatory and other mechanisms.
The importance of inflammation for all stages of atherosclerosis is increasingly recognized and there are data suggesting that grape polyphenols have antiinflammatory effects. For example, red wine and polyphenols inhibit activation of nuclear factor-κB and production of proinflammatory factors in endothelial cells and inflammatory cells (61,68). Incubation of monocytes with catechin decreased their adhesion to endothelial cells (69). Relevant polyphenols also inhibit activation of nuclear factor-κB in T lymphocyte cell lines (70). Resveratrol has also been shown to have antiinflammatory effects, including inhibition of adhesion molecule expression (6,71). In humans, treatment with lyophilized grape powder for 4 wk was associated with a reduction in tissue necrosis factor-α, but not C-reactive protein or interleukin-6 (43). Wine and gin consumption for 4 wk also reduced systemic markers of inflammation in healthy men and the effect was more marked following wine consumption (72). Thus, antiinflammatory effects might be a contributing mechanism for the benefits of grape polyphenols against cardiovascular disease.

Clinical implications
As reviewed in the preceding sections, there is strong epidemiological evidence linking reduced cardiovascular risk with consumption of grapes and other polyphenol-rich foods. Experimental and translational studies suggest several important mechanisms that might account for such an effect. An important remaining question is how to incorporate these data into specific recommendations for dietary intake for the general public. A detailed discussion of these issues is beyond the scope of this review, but a number of factors complicate the formulation of such recommendations at the population level. For example, obtaining an accurate estimate of current intake is confounded by structural diversity, wide distribution in foods, and variations in content of polyphenols (73). Polyphenol bioactivity is further clouded by variable bioavailability due in part to differences in food matrix and human gut absorption (74,75). Ultimately, such efforts are limited, because it remains uncertain which components of polyphenol-rich foods actually confer benefit.

In addition to developing better dietary recommendations, emerging studies showing cardiovascular benefits of polyphenol-rich foods have also prompted interest by the pharmaceutical industry. It is possible that purified formulations of specific grape constituents, e.g. resveratrol, might be efficacious as drugs for cardiovascular disease treatment or prevention. Indeed, such promise has led to identifying synthetic polyphenol analogs that might have greater potency and therapeutic potential. Such compounds will require large-scale trials before they can be approved for clinical use. In the meantime, the available evidence supports a diet rich in fruits and vegetables, including grapes, as an appropriate strategy to reduce the risk of cardiovascular disease.

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