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J Biomed Biotechnol. 2004 December 1; 2004(5): 272–278. doi: 10.1155/S1110724304403088. | PMCID: PMC1082891 |
Effect of Grape Seed Extract and Quercetin on Cardiovascular
and Endothelial Parameters in High-Risk Subjects Peter M. Clifton* CSIRO Health Sciences and Nutrition, CSIRO, PO Box 10041, Adelaide BC, SA 5000, Australia Received March 3, 2004; Revised May 18, 2004; Accepted June 15, 2004. Grape seed extract (GSE) has in vitro antioxidant activity but whether or not
it works in vivo is not clear. In a fully randomised, crossover
trial with 4-week treatment periods on 36 men and women
with above-average vascular risk, we aimed to demonstrate that
2  g/day of GSE (1 g of polyphenols) alone,
or with 1 g/day of added quercetin in yoghurt, favourably alters
vascular function, endothelial function, and degree of oxidative damage
in comparison to a control yoghurt. GSE alone improved flow-mediated
dilatation determined ultrasonically by an absolute 1.1% compared
with control. There was no effect of the combination of GSE with
quercetin. No other blood or urine measure was altered. Thus
sufficient polyphenols from GSE appear to be absorbed to influence
endothelial nitric oxide production, and GSE has the potential to
favourably influence vascular function. Wine polyphenols have been postulated to have many favourable
effects [ 1, 2,
3, 4]
but most of this data has been obtained
in vitro [ 5,
6]. Grape seed extracts (GSEs) contain a high concentration
of many of the polyphenols in grape skins, in particular, the
proanthocyanidins, which are also found in red wine. Green tea also
contains polyphenols, in particular, the catechins, which are believed
to mediate many of the cancer chemopreventive effects [ 7]. Green
tea has been epidemiologically associated with protection from both
cancer and heart disease [ 8]. Although there is abundant in
vitro evidence that polyphenols have antioxidant and anticancer effects,
there is a dearth of animal and human experiments [ 9]. CSIRO
data (unpublished) indicates that GSEs inhibit low-density lipoprotein (LDL) oxidation and reduce aortic ring
constriction in vitro. Extract of oligomeric
proanthocyanidins from other sources such as Pycnogenol from pine
bark enhances nitric oxide (NO) production from vascular endothelium
in vitro [ 10]. Grape seed proanthocyanidin extract (GSPE,
0.1% level) has been shown to reduce atherosclerosis in
cholesterol-fed rabbits by 30%–50% probably by inhibiting LDL
oxidation as lipid levels were not altered while malondialdehyde
levels in the aorta (an index of lipid oxidation) were reduced by
25% [ 11].
Plasma proanthocyanidins were not detectable,
suggesting that absorption is very low. Rats given a dose as a
single bolus do have low (0.5 μM) but detectable
levels. The dose of GSPE was equivalent to a dose of
3.5 g for a 70 kg
human [ 12]. Most over-the-counter forms of
GPSE are in doses of 50–100 mg with a recommendation to take
1 capsule/day. This material has been available for many years
and is regarded as safe and nontoxic. Quercetin, a flavanoid prominent in onions and apples, has been
epidemiologically associated with protection from coronary artery
disease and cancer [ 13,
14] and is now available over the
counter in 300–500 mg dose forms, with daily doses of up to
1500 mg. No clinical trials in the cardiovascular area have been
performed with quercetin although it has been shown to inhibit
monocyte adhesion to endothelial cells [ 15]. This is believed to
be the first step in the process of atherosclerosis. One trial using
4 g/day has shown no effects on lipids, blood pressure, or platelet
activation in normal volunteers [ 16]. In this study we hypothesised that 2 g/day of GSE would
improve flow-mediated dilatation (FMD) and this might be mediated
by changes in the production of NO. We also hypothesised
that GSE and quercetin would function as antioxidants in plasma,
reduce the level of F2 isoprostane in urine, and possibly
influence the level of oxidized LDL in plasma and, secondary to
this, reduce the activation of the endothelium. This would be
assessed by changes in adhesion, clotting, and fibrinolytic molecules. Subjects Forty-three men and women with above-average vascular risk due to high
cholesterol, smoking, or high blood pressure were recruited by
public advertisement and screened at the Clinical Research Unit,
CSIRO Health Sciences and Nutrition, Adelaide. There were no
exclusion criteria on the basis of medication or consumption of
alcohol. Subjects were excluded if their body mass index (BMI)
was greater than 35 or if they suffered from diabetes mellitus, untreated
metabolic disorders such as thyroid or adrenal disease, liver or
kidney disease, or unstable coronary artery disease. All
subjects gave written, informed consent and the protocol was
approved by the Human Ethics Committee of CSIRO. The trial was 12 weeks long and consisted of 3
four-week periods of a double-blind
randomised crossover with
control and active ingredients (1 g GSE from Tarac +/−
0.5 g quercetin) in 240 g of yoghurt taken twice daily.
Blood samples and vascular compliance measures were taken at
baseline and at the end of each period. The background diet was a
low-polyphenol, low-quercetin diet. This was achieved by
restricting tea and coffee to a maximum of 2 cups per day,
restricting apples to one per day, and forbidding red wine and onions
throughout the 12 weeks. Measures included FMD using ultrasound,
vascular compliance using radial pulse analysis (Hypertension
Diagnostics Inc/PulseWave CR-2000), fasting lipids, oxidized
LDL, nitrates (to assess the antioxidant effects), C reactive
protein (CRP), von Willebrand factor (VWF), tissue-type plasminogen
activator (tPA), plasminogen activator inhibitor 1 (PAI-1),
vascular cell adhesion molecule (VCAM1), and intercellular adhesion
molecule 1 (ICAM-1). Twenty-four-hour urine was collected to measure the
oxidized lipid isoprostane F 2α. FMD was assessed in the brachial artery after blockage of blood
flow in the forearm with a blood pressure cuff at 200 mmHg for
5 minutes. The response of the vessel 5 minutes
after administration of 100 μg of glyceryl trinitrate (GTN)
sublingually was also assessed [ 17]. Serum lipids Serum lipids (total cholesterol, triglyceride, HDL cholesterol) were
measured on 2 consecutive days at baseline and at the end of each
3-week intervention period. Venous blood samples (20 mL)
were taken into plain tubes after an overnight fast of 12 hour.
Serum was separated by low-speed centrifugation at 600 g for
10 minutes at 5 °C (GS-6R centrifuge; Beckman,
Fullerton, Calif) and frozen at −20 °C. At the end of
the study, all samples from each subject were analysed within the
same analytic run. Total cholesterol and triacylglycerol were measured
on a Cobas-Bio centrifugal analyzer (Roche Diagnostica, Basel,
Switzerland) using enzymatic kits (Hofmann-La Roche Diagnostica,
Basel, Switzerland) and standard control sera. Plasma HDL-cholesterol
concentrations were measured after precipitation of apoB containing
lipoproteins by PEG 6000. The coefficients of variation
for the individual lipids were all less than 5%. The following
modification of the Friedewald equation for molar
concentrations was used to calculate LDL cholesterol in
mmol/L: total cholesterol—(triacylglycerol/2.18)—HDL cholesterol. All other tests were enzyme linked immunosorbent assays (ELISAs): VWF
(Helena Laboratories, Melbourne Australia), Coaliza tPA (Chromogenix, Sweden),
Coaset tPA (Chromogenix), Coaliza PAI-1 (Chromogenix),
Coatest PAI-1 (Chromogenix), oxidised LDL: Mercodia oxidised LDL ELISA (Mercodia, Sweden), SVCAM1
(Immunokontact, Sweden), ICAM1 (Immunokontact), CRP (Alpha
Diagnostic International, Texas), 8-isoprostane (8-iso PGF2α)
(Cayman Chemical), nitrate/nitrite assay kit (Cayman Chemical). Statistical analysis Repeated measures analysis of variance was
calculated with type of yoghurt as the within-subject factor and
with sex and order as the between-subject factors. Where there
was a significant treatment effect detected by repeated measures,
paired Student  tests were used to locate differences.
Bivariate correlation was conducted using
Pearson's correlation coefficient. Analyses were performed
with SPSS 10.0 for Windows (SPSS Inc, Chicago, Ill).
Significance was set at  . Twelve women and twenty-four men completed the study and one additional
woman missed the last phase of treatment. Six subjects withdrew after
commencement and 6 withdrew prior to commencement. The risk profile of subjects was as follows: 6 subjects had high blood pressure (5
on medication), 3 were smokers, and 31 had high cholesterol
(greater than 5 mmol/L on finger prick). Two volunteers on atorvastatin to
lower cholesterol stopped the medication prior to beginning the trial.
The average cholesterol was 6.5 mmol/L (range 4.68 to 8.63),
average age 58 years (range 34–70), weight 83.1 Kg
(63.1 kg to 118.7 kg), BMI 28.4 (19.8–37.5). Mean
blood pressure was 127 mm Hg systolic and 74 mm Hg diastolic. Blood pressure/vascular compliance There was a weak (  ) trend to a lowering of systolic blood
pressure over the duration of the trial with a fall from 127 mm Hg
at baseline to 124 mm Hg at week 12. This is quite usual in
clinical trials in which blood pressure is measured. There were
no changes in any vascular parameter with
treatment (see Table 1). | Table 1Cardiovascular measures produced by the HDI compliance
instrument; mean of 35 complete measures ± SD. |
Flow-mediated dilatation after compression release and GTN dilatation GSE alone produced an absolute 1.1% greater
dilatation compared with control (  ) but the addition of
quercetin apparently nullified this completely. GTN-induced
dilatation was not influenced by GSE but quercetin again appeared
to diminish the response compared with baseline (  ), but not compared with control. This indicates that GSE favourably influences the endothelium
enhancing NO production, release or slowing down
oxidative destruction of it, but quercetin appears to interfere
with this. It is known that quercetin inhibits LPS-induced NO
release in RAW 264.7 macrophages [ 18] and can act as a prooxidant
in other systems [ 19,
20, 21] at both low and high
levels (see Table 2). | Table 2Flow-mediated dilatation as measured by ultrasound. N = 35, mean SD. Treatments with different superscripts are different at  . |
Serum lipids No changes were noted but none were expected. Subjects were at
high risk of cardiovascular disease by virtue of the high average
cholesterol (see Table 3). | Table 3Effect of GSE and GSE/quercetin on serum lipids mean (mmol/L) ± SD. |
C reactive protein CRP is an acute-phase protein produced by the liver in response
to tissue damage or inflammation and may increase 500 fold
acutely [ 22]. It is also elevated but to low levels by low-grade
inflammatory conditions such as atherosclerosis and can be used
to predict clinical events [ 23]. Statins which lower cholesterol
by inhibiting synthesis in the liver also lower CRP and the mechanism
appears to be unrelated to the degree of cholesterol lowering
[ 24]. It may be related to their antioxidant activity or a
direct anti-inflammatory activity. Thus in this study it was used to
check both for potential toxic effects and to demonstrate a
potential of GSE to act like a statin in the vessel wall. No
differences were found between periods or treatments. One person was
excluded as he had a respiratory infection requiring antibiotics
which caused a sharp rise in CRP levels (over a 100-fold rise)
(see Table 4). | Table 4Effect of GSE and GSE/quercetin on plasma CRP,
nitrate/nitrite, and adhesion molecules. N = 35, mean SD. |
Nitrate/Nitrite Plasma nitrate was measured as a surrogate index of NO
production [ 25,
26]. NO is an endogenous
vasodilator produced by endothelial cells. Red wine polyphenols
enhance vasorelaxation and NO production in vitro
[ 27, 28].
Ethanol itself also enhances NO production
[ 29]. No differences were found either by period
or by treatment with or without an outlier whose value rose
6-fold in the GSE period. However, dietary nitrites and nitrates
can confound this measure quite easily so the absence of change
does not mean that NO production did not rise
(see Table 4). Adhesion molecules ICAM1 and VCAM1 are molecules which bind white cells to the
endothelium and reflect the state of the health of the
endothelium, particularly in relationship to atherosclerosis
[ 30,
31]. If the endothelium is damaged by oxidized lipid,
cigarette smoke, or high blood pressure, these markers increase
[ 32]. An antioxidant might be expected to lower the level of
these markers (vitamin E does in some studies [ 33]) as does a
statin which lowers plasma lipid level [ 34]. Polyphenols from
blue and red berries reduce adhesion molecules in endothelial
cells in vitro [ 35]. GSE and GSE/quercetin had no effect, nor
were there any time effects (see Table 4). Clotting and fibrinolytic factors VWF mediates the binding of platelets to injured vessels and
protects coagulation factor VIII. It is produced in the endothelium
and is released when the endothelium is damaged by atherosclerosis,
diabetes, insulin resistance, or hypertension [ 36,
37, 38].
Tissue-type plasminogen activator is released from endothelial
cells to initiate the process of breaking down clots in the vessel
by activating plasminogen to plasmin which then breaks down fibrin.
Endothelial dysfunction impairs the release of active tPA [ 39]
and is associated with an enhanced release of PAI-1 [ 40]. GSE and
GSE/quercetin had no effect on VWF, tPA, or PAI-1 and there were no time effects.
In [ 41] de Maat et al found no effect of black or green tea on any of the
markers we measured, but wine polyphenolics have been shown in
cultured human endothelial cells [ 42] to increase production of
tPA (see Table 5). | Table 5Effect of GSE and GSE/quercetin on clotting and
fibrinolytic factors. N = 35, mean SD. |
Urine isoprostanes 8-Isoprostane (8-iso PGF2 α) is a stable end product formed from
arachidonic acid by free radical action and is measurable in
plasma and urine. The level is believed to represent the degree
of oxidative stress in lipids [ 43,
44]. In this experiment, we saw no changes in urinary isoprostanes either
absolute or expressed in relation to creatinine to adjust for
incomplete urinary collections (see Table 6). The values
measured in this study were in the range described for subjects
with type 2 diabetes. Vitamin E has been shown to reduce plasma
and urine isoprostanes in some studies [ 45,
46] but not in
others [ 47]. Subjects with type 2 diabetes have elevated
(double) level of urinary isoprostane compared with controls
and it falls by 32% with treatment with
vitamin E [ 48]. Ide et al
[ 49] found that in healthy young men vitamin E could reduce
urine isoprostane levels by 48%. Whole grains have been found to
lower isoprostane by 28% in one study [ 50], as did fruit and
vegetables in another study [ 51], although van den Berg found
no effects of fruit and vegetables [ 52]. Tea polyphenols did
not alter isoprostanes [ 53] while dealcoholised red wine reduced
the levels in plasma with a trend in urine [ 54]. | Table 6Effect of GSE and GSE/quercetin on urine isoprostane
(iso PGF2α). N = 35, mean SD. |
Although the results are negative except for the FMD changes, they
are not incompatible with the current literature which is not
uniform in its results. They are also compatible with the
observed lack of change in the levels of oxidized LDL
(see Table 7) in this study. There is no published data on
measurement of oxidized LDL in plasma using this method. | Table 7Effect of GSE and GSE/quercetin on oxidised LDL levels U/L; N = 35, mean SD. |
There were no changes in urine chemistry, haematology, clotting,
or biochemistry with GSE or GSE/quercetin. There were some
time-related changes in urea and creatinine chloride and
bicarbonate which may have been due to warmer weather (data not shown). We have demonstrated that sufficient antioxidant polyphenols from
GSE were absorbed to influence FMD but no other endothelial
functions were affected. It is known from rat and rabbit studies
that the absorption of proanthycyanidins from GSE is very
limited. In one rat study [ 55],
after feeding 0.25 g/kg of
GSE (equivalent to feeding over 20 g to humans), a level of
18 μg/mL of dimer was achieved after 1 hour. In the
rabbits, despite an equivalent dose spread over the day, no
proanthocyanidins were detected, even though in this model lipid
peroxidation and aortic atherosclerosis were reduced [ 11]. In
vitro studies often use levels of 10–50 μg/mL [ 6] which is 10–20 times higher than what might be achieved in human
studies. Quercetin is known to be absorbed and 1 g/day can produce
levels 23 times higher than control capsules. Despite this level
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