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Quercetin Reduces Blood Pressure in Hypertensive Subjects

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Epidemiological studies report that quercetin, an antioxidant flavonol found in apples, berries, and onions, is associated with reduced risk of coronary heart disease and stroke. Quercetin supplementation also reduces blood pressure in hypertensive rodents. The efficacy of quercetin supplementation to lower blood pressure in hypertensive humans has never been evaluated. We tested the hypothesis that quercetin supplementation reduces blood pressure in hypertensive patients. We then determined whether the antihypertensive effect of quercetin is associated with reductions in systemic oxidant stress. Men and women with prehypertension (n = 19) and stage 1 hypertension (n = 22) were enrolled in a randomized, double-blind, placebo-controlled, crossover study to test the efficacy of 730 mg quercetin/d for 28 d vs. placebo. Blood pressure (mm Hg, systolic/diastolic) at enrollment was 137 +/- 2/86 +/- 1 in prehypertensives and 148 +/- 2/96 +/- 1 in stage 1 hypertensive subjects. Blood pressure was not altered in prehypertensive patients after quercetin supplementation. In contrast, reductions in (P < 0.01) systolic (-7 +/- 2 mm Hg), diastolic (-5 +/- 2 mm Hg), and mean arterial pressures (-5 +/- 2 mm Hg) were observed in stage 1 hypertensive patients after quercetin treatment. However, indices of oxidant stress measured in the plasma and urine were not affected by quercetin. These data are the first to our knowledge to show that quercetin supplementation reduces blood pressure in hypertensive subjects. Contrary to animal-based studies, there was no quercetin-evoked reduction in systemic markers of oxidative stress.
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The Journal of Nutrition
Nutrition and Disease
Quercetin Reduces Blood Pressure in
Hypertensive Subjects
1,2
Randi L. Edwards,
3
Tiffany Lyon,
3
Sheldon E. Litwin,
4
Alexander Rabovsky,
6
J. David Symons,
3,5
and Thunder Jalili
3
*
3
Division of Nutrition,
4
Division of Cardiology, and
5
Department of Exercise and Sports Science, University of Utah, Salt Lake City,
UT 84112 and
6
USANA Health Sciences, Salt Lake City, UT 84120
Abstract
Epidemiological studies report that quercetin, an antioxidant flavonol found in apples, berries, and onions, is associated
with reduced risk of coronary heart disease and stroke. Quercetin supplementation also reduces blood pressure in
hypertensive rodents. The efficacy of quercetin supplementation to lower blood pressure in hypertensive humans has
never been evaluated. We tested the hypothesis that quercetin supplementation reduces blood pressure in hypertensive
patients. We then determined whether the antihypertensive effect of quercetin is associated with reductions in systemic
oxidant stress. Men and women with prehypertension (n¼19) and stage 1 hypertension (n¼22) were enrolled in a
randomized, double-blind, placebo-controlled, crossover study to test the efficacy of 730 mg quercetin/d for 28 d
vs. placebo. Blood pressure (mm Hg, systolic/diastolic) at enrollment was 137 62/86 61 in prehypertensives and 148 6
2/96 61 in stage 1 hypertensive subjects. Blood pressure was not altered in prehypertensive patients after quercetin
supplementation. In contrast, reductions in (P,0.01) systolic (2762mmHg),diastolic(2562 mm Hg), and mean arterial
pressures (2562 mm Hg) were observed in stage 1 hypertensive patients after quercetin treatment. However, indices of
oxidant stress measured in the plasma and urine were not affected by quercetin. These data are the first to our knowledge to
show that quercetin supplementation reduces blood pressure in hypertensive subjects. Contrary to animal-based studies,
there was no quercetin-evoked reduction in systemic markers of oxidative stress. J. Nutr. 137: 2405–2411, 2007.
Introduction
Quercetin is a flavonol that belongs to a group of polyphenolic
compounds known as flavonoids (1). Widespread epidemiolog-
ical evidence indicates that quercetin contained in onions, apples,
berries, and red wine aids in preventing cardiovascular disease
and stroke (2–8). Along with these promising data, recent
laboratory studies have demonstrated that quercetin has impor-
tant vasorelaxant properties on isolated arteries and lowers blood
pressure in the spontaneously hypertensive rat (9,10). In addition,
we have shown that quercetin administered to rats prevents the
development of hypertension and cardiac hypertrophy in re-
sponse to pressure overload created by abdominal aortic
constriction (11). The beneficial effects of quercetin concerning
vasorelaxation and blood pressure in rodents have been attrib-
uted at least in part to the ability of this flavonoid to decrease
indices of oxidative stress (9,11,12).
Despite existing epidemiological and animal-based research
concerning quercetin and cardiovascular disease, no studies have
evaluated whether quercetin supplementation lowers blood
pressure in hypertensive humans. Therefore, we performed a
randomized, placebo-controlled crossover trial to test the
hypothesis that quercetin reduces blood pressure in prehyper-
tensive and stage 1 hypertensive subjects. Systemic markers of
oxidant load also were examined as secondary outcomes to
determine whether reductions in blood pressure were associated
with lower indices of oxidative stress.
Materials and Methods
Participants and recruitment criteria
This study was approved by the University of Utah Human Use Review
Committee, University of Utah Institutional Review Board, and written
informed consent was obtained from each participant. Recruitment
efforts in the greater Salt Lake City area targeted males and females with
prehypertension (120–139 mm Hg systolic/80–89 mm Hg diastolic) and
stage 1 hypertension (140–159 mm Hg systolic/90–99 mm Hg diastolic)
as defined by the 7th Report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure (13). Figure 1 summarizes the number of subjects screened,
recruited, and enrolled in this study. Initial screening consisted of asking
volunteers if they had a history of high blood pressure, followed by a
single blood pressure measurement using an Omron random zero blood
pressure analyzer. If blood pressure criteria were met during the initial
screening, subjects were referred to the Nutrition Clinic for further
1
Supported by a University of Utah Technology Commercialization Office grant
and NIH 085226 (T.J.). J.D.S. is supported by an AHA Western States Affiliate
Grant-In-Aid (0655222Y).
2
Author disclosures: R. L. Edwards, T. Lyon, S. E. Litwin, A. Rabovsky, J. D.
Symons, no conflicts of interest; T. Jalili, patent pending on the use of quercetin
as an antihypertensive agent.
* To whom correspondence should be addressed. E-mail: thunder.jalili@utah.
edu.
0022-3166/07 $8.00 ª2007 American Society for Nutrition. 2405
Manuscript received 15 May 2007. Initial review completed 20 June 2007. Revision accepted 14 August 2007.
at Univ of Utah Serials Dept/Eccles Health Sci Lib on October 19, 2007 jn.nutrition.orgDownloaded from
evaluation of blood pressure and confirmation of eligibility criteria.
Subjects who met blood pressure guidelines and eligibility criteria after
the clinical evaluation were enrolled in the study. We recruited
participants from October 2004 to June 2005. Forty-four patients who
met study criteria consented and were enrolled, 21 prehypertensive and
23 stage 1 hypertensive. Forty-one subjects completed the entire protocol
and 3 withdrew (1 male and 1 female from the prehypertensive group
and 1 male from the stage 1 hypertensive group).
Subjects were excluded based on their current use of antihypertensive
medication. Major exclusion criteria for hypertensive subjects included
current smoking, history of a prior cardiovascular event, diabetes, renal
insufficiency, hyperlipidemia (total cholesterol .240 mg/dL), pregnancy,
lactation, any chronic disease that might interfere with study participa-
tion, BMI above 35 kg/m
2
, consumption of .12 alcoholic drinks weekly,
or unwillingness to stop current supplement intake or use of calcium/
magnesium antacids. All subjects who met exclusion criteria agreed to
maintain their typical diet and exercise habits.
Objectives, interventions, and outcomes
The primary hypothesis to be tested was that 365 mg quercetin aglycone
taken twice per day reduces blood pressure in prehypertensive and stage
1 hypertensive subjects. The secondary hypothesis was that quercetin-
induced reductions in blood pressure would be associated with lower
indices of systemic oxidant stress. Participants chosen from the initial
screening process were scheduled for a familiarization visit to the clinic
at the University of Utah Nutrition Laboratory. During that visit
participant responsibilities were explained, consent was obtained, and
blood pressure status was verified. Subjects were then instructed to
discontinue any existing supplement use and complete a 14-d run-in
period (Fig. 1). After the run-in period, they were enrolled in a double
blind, placebo-controlled, crossover trial consisting of a 4-wk quercetin
supplementation phase and a 4-wk placebo phase. A 14-d washout
period separated the 2 phases. To validate that a 2-wk washout period
was sufficient to reduce plasma quercetin to baseline, 5 subjects con-
sumed quercetin supplements for 1 wk, followed by a 1-wk washout
period. We then measured plasma quercetin concentrations to determine
whether quercetin levels were similar to those who had not taken
quercetin.
Subjects were randomly assigned to begin either the quercetin or the
placebo phase first. Four-week treatment phases were chosen because
this duration has been shown to be efficacious concerning dietary
interventions (14). Clinic visits were conducted on overnight-fasted
subjects in the morning hours at the beginning and end of the placebo
and quercetin supplementation phases. Subjects were instructed not to
exercise prior to their appointments. Compliance was confirmed by a
tablet count at the completion of each phase of the study and by
quantifying plasma quercetin concentrations.
Because no human studies have examined whether quercetin reduces
blood pressure in hypertensive humans, the dose of quercetin used in this
trial was based on efficacious results we and others have obtained using
animal models of hypertension (9,12,15). Tablets containing placebo or
quercetin were manufactured by USANA Health Sciences (Table 1).
Blood pressure measurement
Blood pressure was a primary outcome variable and was obtained at
each clinic visit by a trained observer using an Omron random zero
automatic blood pressure analyzer as previously described (16). Each
participant sat quietly for 5–10 min, after which their arm was placed at
heart level and blood pressure and pulse rate were measured at least 3
times in 3- to 5-min intervals. If blood pressure varied in these
determinations by .10 mm Hg, 3 additional trials were performed to
measure systolic and diastolic blood pressure. The accumulated mea-
surements then were averaged to determine overall systolic and diastolic
pressure and pulse rate for each subject.
Venous blood collection
Blood samples were collected after blood pressure was measured. We
collected blood by antecubital venipuncture from fasting subjects into
sodium heparin tubes (Becton Dickinson). Collected blood was imme-
diately stored on ice and centrifuged within 10 min at 2500 3g; 15 min
at 4C as previously described (17). Plasma was separated and stored at
280C until it was analyzed for quercetin concentration, plasma anti-
oxidant reserve (PAR), and ferric reducing antioxidant power (FRAP).
Blood lipid, glucose, and urine collection
During each patient visit, whole blood (;50 mL) was obtained from a
digit puncture to determine blood lipid concentrations (triglycerides;
LDL, VLDL, HDL, and total lipoprotein concentrations) and glucose
using a clinical Cholestech LDX blood analyzer (18). These outcomes
were quantified because earlier studies have reported beneficial changes
in the blood lipid profile of quercetin-supplemented rats that consumed a
cholesterol-rich diet (19). Prior to each patient visit, first morning urine
was collected, brought to the laboratory, and stored at 280C for later
analysis of isoprostane concentrations.
Quercetin analysis
Plasma quercetin was analyzed as previously described (20) with slight
modifications; 250 mL samples were hydrolyzed with 100 mL and 500
mL of 6 mol/L HCl. Supernatants then were extracted with ethyl acetate
and injected into an HPLC Discovery C18 column. The mobile phase
was 1% acetic acid (solvent A) and 95% acetonitrile in 1% phosphoric
FIGURE 1 Summary of subject recruitment and experimental
design.
TABLE 1 Composition of quercetin and placebo tablets
Placebo Quercetin
mg/tablet
Quercetin with corn starch 0 364
Microcrystalline cellulose 564 192
Dicalcium phosphate 312 312
Colloidal silicon dioxide 6 6
Ascorbyl palmitate 6 14
Croscarmellose sodium 12 12
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acid (solvent B). The gradient elution used was solvent B from 10 to 85%
over 20 min, and then held for 5 min before returning back to 10% for
conditioning. A visible detector with 365 nm was used and quercetin was
quantified by peak height ratio method.
Indices of oxidative stress
PAR. Ex vivo amplification of isoprostanes was accomplished by
introducing a source of free radicals (3-morpholinosydnonimine) into
the blood plasma to induce oxidation of lipoproteins (21). Uric acid, a
major water soluble antioxidant present in plasma, was removed using
uricase prior to introduction of 3-morpholinosydnonimine so that any
protection provided by other antioxidants could be measured. Therefore,
PAR measures the non-urate antioxidant capacity, or antioxidant power,
of blood. It has been previously demonstrated that supplementing anti-
oxidants can increase the antioxidant capacity of the blood as deter-
mined by PAR (21).
FRAP. FRAP measures the ability of an antioxidant to reduce Fe
31
to
Fe
21
(22) and is an index of plasma antioxidant potential in hypertensive
patients (23–26). This assay was done as previously described (21).
Briefly, plasma samples were diluted 1:2 with PBS, followed by addition
of a reagent solution containing 0.8 mmol/L 2,4,6-tri-(2-pyridyl)-s-
tirazine and 1.7 mmol/L FeCl
3
6-H
2
O. Samples were then incubated at
37C for 15 min and the absorbance at 593 nm was recorded in a plate
reader (Molecular Devices, Spectramax 340 pc).
Urinary isoprostane measurement. Urine 8-isoprostane F2ais a
measure of lipid peroxidation and can be used to estimate oxidative
stress in hypertensive humans (27–29). Quantification of 8-isoprostane
F2a(also known as 8-epi-PGF2aor 8-iso-PGF2a) in urine samples was
performed using a competitive enzyme-linked immunoassay kit (Cay-
man Chemical) according to the manufacturer’s instructions.
Dietary analysis
Three-day dietary records were obtained from each subject during the
last 14 d of both placebo and quercetin treatment. All records were
analyzed using the Food Processor dietary analysis program (ESHA
Research) (30).
Statistical analyses
All data are reported as means 6SEM. All variables were analyzed using
paired ttests to detect differences within the placebo and quercetin
treatment phases (i.e. baseline vs. endpoint) (SPSS v.11.0.3). Dietary
intake data and plasma quercetin concentrations were examined using
paired ttests comparing placebo vs. quercetin phases. Regression
analyses using age, gender, BMI, PAR, FRAP, and urinary isoprostane
F2aconcentration as independent variables and systolic blood pressure
as the dependent variable were performed. Systolic pressure was selected
as the dependent variable, because it has been identified as a better
predictor of cardiovascular disease than diastolic pressure (13). Differ-
ences were considered significant at P,0.05.
Results
Patient characteristics. Nearly 1000 patients were interviewed
and screened for eligibility. The majority (i.e. ;800) were not
considered further for participation because they met 1 or more
of the exclusion criteria or did not have blood pressure within
study limits. From this initial screening, 204 individuals were
evaluated in more detail at a subsequent clinic visit to determine
whether all inclusion/exclusion criteria were met and if blood
pressure was within the study limits (Fig. 1). Forty-four subjects
were initially enrolled and 41 completed the entire 12-wk study.
The age of prehypertensive (n¼19, n¼13 males) and stage
1 hypertensive (n¼22, n¼13 males) subjects was 47.8 63.5
and 49.2 62.9 y old, respectively. No adverse effects of
quercetin or placebo treatment were reported during the course
of the study. Weight and BMI did not change between treatments
in either group (Table 2). Heart rate was unchanged throughout
the study (data not shown).
Plasma quercetin was 695 6103 nmol/L after placebo
treatment and increased to 1419 6189 nmol/L after quercetin
treatment. Our preliminary experiments indicated that a 1-wk
washout period was sufficient to bring plasma quercetin concen-
trations to 562 627 nmol/L. These values are similar to those
obtained from subjects who consumed placebo but had not yet
been exposed to quercetin. There was also no effect of treatment
order on the observed changes in blood pressure (r¼0.194; P¼
0.388), indicating that the antihypertensive effect of quercetin did
not persist in those who received quercetin supplements before
placebo.
Blood pressure. Placebo treatment did not alter blood pressure
in either group of hypertensive subjects. Blood pressure was
TABLE 2 Body mass and biomarkers of oxidative stress in prehypertensive and stage 1 hypertensive
subjects before and after supplementation with quercetin and placebo
1
Weight BMI Urinary isoprostane Plasma FRAP Plasma PAR
Prehypertensive–placebo kg kg/m
2
nmol/mol creatine mmol/L ng/L
n19 19 8 8 8
Baseline 91.6 65.3 29.8 61.3 1.53 60.21 1180 659 346 632
Endpoint 91.6 65.4 29.7 61.3 1.69 60.26 1028 662 321 658
Prehypertensive–quercetin
n19 19 8 8 8
Baseline 91.6 65.3 29.6 61.3 1.46 60.16 1089 656 308 655
Endpoint 91.6 65.2 29.7 61.2 1.47 60.21 1072 668 280 637
Stage 1 hypertensive–placebo
n22 22 8 8 8
Baseline 88.7 64.4 29.5 61.4 1.67 60.42 1096 670 285 660
Endpoint 88.0 64.4 29.4 61.4 2.57 61.00 1086 666 238 652
Stage 1 hypertensive–quercetin
n22 22 8 8 8
Baseline 88.7 65.5 29.3 61.3 2.32 60.70 1056 659 258 655
Endpoint 88.2 65.5 29.5 61.4 1.55 60.17 1152 669 281 674
1
Values are means 6SEM. There were no changes in either group during either phase of the study.
Quercetin reduces blood pressure 2407
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similar in prehypertensive subjects compared with placebo after
quercetin treatment. In contrast, quercetin supplementation
reduced systolic, diastolic, and mean arterial pressure in stage
1 hypertensive subjects (Fig. 2A,B;Table 3). The antihyperten-
sive effect of quercetin was independent of gender (r¼0.343;
P¼0.118), age (r¼0.202; P¼0.381), and BMI (r¼0.061; P¼
0.788) in stage 1 hypertensive subjects.
Indices of oxidative stress and antioxidant capacity.
Measurements of antioxidant capacity (fasting plasma FRAP
and PAR) and oxidative stress (fasting urinary 8-isoprostane F2a
concentration) within either placebo or quercetin supplementa-
tion phases were not altered (Table 2). The antihypertensive
effect of quercetin was independent of PAR (r¼0.367; P¼
0.093), FRAP (r¼0.02; P¼0.930), and urinary 8-isoprostane
F2a(r¼0.353; P¼0.437) in stage 1 hypertensives.
Dietary analyses. Three-day diet record analysis indicated that
there was lower vitamin K intake during the quercetin phase vs.
placebo in prehypertensive patients (Table 4). Stage 1 hyperten-
sive subjects had reductions in potassium intake during the
quercetin supplementation vs. placebo phase (Table 4). All other
nutrients evaluated were similar in placebo vs. quercetin phases
in both groups of hypertensive subjects.
Fasting plasma lipids and glucose. Concentrations of plasma
triglycerides and total, LDL, VLDL, and HDL cholesterol, and
fasting blood glucose concentrationsdid not change after quercetin
supplementation or after placebo treatment in prehypertensive or
stage 1 hypertensive patients (Tab le 5). The total cholesterol:HDL
cholesterol ratio was also unchanged (data not shown).
Discussion
Results from this investigation support our primary hypothesis
and are the first to our knowledge to demonstrate that daily
supplementation with 730 mg quercetin for 28 d reduces
systolic, diastolic, and mean arterial pressure in subjects with
stage 1 hypertension. These findings are an important extension
of previous studies showing that quercetin lowers blood pressure
in hypertensive animals (9,11,12,31,32) and prevents the onset
of hypertension in response to mechanical overload in rodents
(11). The antihypertensive effect of quercetin in our subjects
may also explain at least in part why previous epidemiological
reports show an inverse relationship between dietary flavonoid
intake and heart disease risk (1–8,33–37). In contrast to results
obtained from in vitro experiments and animal models
(9,11,12,31,32,38), we did not observe a quercetin-evoked
reduction in oxidative stress as determined by plasma PAR,
FRAP, and urinary isoprostanes.
To our knowledge, only 1 other study has examined the effect
of quercetin supplementation in humans (39). In that investiga-
tion, Conquer et al. (39) reported no changes in blood pressure
when normotensive individuals (i.e. ,120 mm Hg systolic/,80
mm Hg diastolic) were supplemented with 1000 mg/d of
quercetin for 8 wk, despite similar plasma quercetin concentra-
tions (1262 6263 nmol/L) compared with our study (1419 6
189 nmol/L). These data indicate a certain degree of hyperten-
sion might be required for quercetin to exert a blood pressure-
lowering effect. This possibility is supported by data from the
present study wherein quercetin reduced systolic, diastolic, and
mean arterial pressure in stage 1 hypertensive subjects but not in
those with prehypertension. Likewise, animal-based studies
have demonstrated that quercetin is efficacious in lowering
blood pressure in hypertensive but not normotensive rats (9,11).
Three-day diet records were used to evaluate whether
changes in nutrient intake influenced blood pressure during the
quercetin treatment phase. Though stage 1 hypertensive subjects
had decreased intake of potassium and prehypertensives con-
sumed less vitamin K during the quercetin phase, it is unlikely
that these changes led to reduced blood pressure. With regard to
dietary intake of polyphenolic compounds, it is not possible to
FIGURE 2 Mean arterial blood pressure at baseline and after quercetin and placebo treatments in prehypertensive (A,n¼19) and stage
1 hypertensive (B,n¼22) subjects. Upper graphs illustrate individual subject responses during each supplementation phase; the lower graphs
show means 6SEM. *Different from baseline, P,0.05. MAP, Mean arterial pressure.
2408 Edwards et al.
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determine intake of items such as quercetin, because there are no
suitable databases available for such an analysis. The lack of
databases likely can be attributed to the variation in chemical
composition of fruits and vegetables, coupled with the lack of
sufficiently accurate analytical tools (33). Despite these limita-
tions, it has been estimated that average dietary intake of
quercetin from Western diets is 28–42 mg/d (33,35,36). Intake
of polyphenolic compounds in individual diets is likely depen-
dent on fruit, vegetable, and whole grain consumption and
variations in these foods would be reflected in the vitamin,
mineral, and fiber content reported. Because these dietary
variables were generally similar in subjects during the placebo
and quercetin phases of the study, we believe that intake of
polyphenolic compounds did not differ in participants in our
investigation.
Recent AHA statistics estimate that over 50 million Amer-
icans suffer from hypertension (38). There is a linear relationship
between blood pressure and mortality from stroke and ischemic
heart disease that emphasizes the importance of blood pressure
control (40). Based on risk assessment summarized in the 7th
Report of the Joint National Committee on Prevention, Detec-
tion, Evaluation, and Treatment of High Blood Pressure, the risk
of death from ischemic heart disease and stroke in prehyperten-
sive patients used in the present study is double that of
individuals with blood pressure of 115/75 mm Hg and nearly
4 times greater in stage 1 hypertensive patients (13). The
quercetin-induced lowering of systolic blood pressure observed
in stage 1 hypertensive subjects (27.2 mm Hg) is clinically
relevant because reductions of this magnitude are associated
with a decrease in mortality of ;14% from stroke and ;9%
from coronary heart disease (40). These findings are noteworthy
in light of the emergence of systolic blood pressure as a more
important risk factor than diastolic pressure with regard to
mortality from cardiovascular disease, particularly in individ-
uals aged .50 y (13).
Lifestyle modification has been emphasized in prehyperten-
sive and hypertensive individuals as an initial intervention to
control blood pressure (13). Interestingly, the reduction of blood
pressure we observed in stage 1 hypertensive subjects after
quercetin supplementation is similar to those experienced
following sodium reduction, weight reduction, increased phys-
ical activity, or alcohol reduction (41). Other proven lifestyle
modifications such as the Dietary Approaches to Stop Hyper-
tension diet result in similar or slightly greater blood pressure
reduction (41). Thus, it appears that the effects of quercetin
supplementation are consistent with current recommended
lifestyle modifications used to reduce blood pressure.
Our secondary hypothesis was that the antihypertensive
effect of quercetin would be associated with a reduction of
systemic oxidant stress. Rationale for this hypothesis was based
on studies showing that quercetin lowers indices of oxidative
stress in a dose-dependent manner in spontaneously hyperten-
sive rats (e.g. lower urinary isoprostanes and plasma malon-
dialdehyde) (9) and nitric oxide-deficient rats (e.g. reduced
plasma malondialdehyde and glutathione peroxidase activity)
(12). Instead, we observed that plasma antioxidant potential
(FRAP and PAR analyses) and urinary 8-isoprostane F2awere
similar in prehypertensive and stage 1 hypertensive subjects
regardless of quercetin or placebo treatment. We do not think
that the lack of an antioxidant effect by quercetin treatment was
due to the dose we used, because it was similar (730 mg/d, ;8.5
mg/kg) to the concentration used in previous animal studies (10
mg/kg) wherein antioxidant effects were demonstrated
(9,12,15). Nevertheless, species-dependent differences in me-
tabolism of quercetin (human vs. rat) may exist. Because local
increased vascular and renal oxidative stress have been reported
in hypertensive animals (42,43), it is possible that humans in our
studies also had elevated oxidative stress in these compartments
despite our observation that urinary isoprostanes were un-
changed. Vascular and renal oxidative stress are difficult to
assess in humans and, as such, we cannot rule out the possibility
that quercetin might have produced local effects that were not
detected using our global measures of oxidative stress (i.e.
urinary isoprostanes).
An important consideration for the present study is the
severity of oxidant stress in our hypertensive subjects. In this
regard, plasma FRAP was similar between both groups of
TABLE 3 Blood pressure in prehypertensive and stage
1 hypertensive subjects before and after
supplementation with quercetin and placebo
1
Prehypertensive, n¼19 Stage 1 Hypertensive, n¼22
Systolic Diastolic Systolic Diastolic
mm Hg
Blood pressure
at enrollment
137 628661 148 629661
Placebo
Baseline 135 638461 141 629462
Endpoint 131 638761 138 629362
Quercetin
Baseline 132 618561 145 629761
Endpoint 128 638462 138 62* 92 62*
1
Values are means 6SEM. *Different from quercetin baseline, P,0.01 (paired
ttest).
TABLE 4 Analysis of 3-d dietary records from prehypertensive
and stage 1 hypertensive subjects after
supplementation with quercetin and placebo
1
Prehypertensive,
n¼18
2
Stage 1 hypertensive,
n¼21
2
Placebo Quercetin Placebo Quercetin
Energy, kJ/d 9043 6553 9663 6829 8776 6645 8156 6620
Protein, g/d 91 65896887658366
Fat, g/d 74 67846980667266
Saturated fat, g/d 24 63276324622262
Polyunsaturated fat, g/d 96196112621062
Monounsaturated fat, g/d 20 62186219621862
Fiber, g/d 21 61246222632264
Carbohydrate, g/d 292 619 309 627 252 627 244 623
Cholesterol, mg/d 267 634 265 635 232 628 221 628
Vitamin C, mg/d 172 628 146 618 164 656 103 616
Vitamin E, mg/d 13 62176315641463
Vitamin K, mg/d 55 613 114 632* 64 622 43 68
Calcium, mg/d 1075 6101 1015 6136 1039 695 966 6128
Magnesium, mg/d 288 639 271 641 276 624 261 629
Sodium, mg/d 2942 6303 3482 6464 2794 6253 3153 6238
Potassium, mg/d 3035 6185 2580 6200 2465 6239 2195 6234*
Selenium, mg/d 79 68656986612 79 612
Zinc, mg/d 10 61961961861
1
Values are means 6SEM. *Different from placebo, P,0.05 (paired ttest).
2
Diet records from 1 patient in the prehypertensive group and from 1 in the stage 1 hy-
pertensive group were not collected.
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hypertensive subjects (1065–1130 mmol/L) from our present
trial and normotensive subjects (973–1064 mmol/L) that were
evaluated in a previous study using identical methods (21).
These data indicate that the cohort evaluated in the present
investigation did not have elevated oxidant stress, at least in
terms of FRAP. As such, the ability of quercetin to further reduce
markers of oxidative stress may be limited. Evidence does exist,
however, for a mechanism involving angiotensin converting
enzyme. For example, 30 mg/kg quercetin (p.o.) in rats signif-
icantly blunted the hypertensive response to i.v. administration
of angiotensin I (44). Although it is possible that higher systemic
concentrations of quercetin, as observed in our study, could limit
angiotensin II production and lower blood pressure, further
investigation would be required to confirm this speculation.
Our study is, to our knowledge, the first to show that
quercetin reduces blood pressure in stage I hypertensive indi-
viduals. Though we used a powerful experimental design
(double blinded, placebo-controlled, crossover) and found
quercetin supplementation to be efficacious in reducing blood
pressure, extrapolation of our results to the general population
should be done with caution given the homogeneous cohort
(middle-aged, Caucasian men and women) and modest sample
size. Nevertheless, our data indicate that potential exists for this
polyphenolic compound to be used as adjunct therapy in diet/
lifestyle interventions to help control blood pressure in hyper-
tensive individuals.
Acknowledgments
The authors thank Dr. Tim Wood of USANA Health Sciences
for the kind gift of placebo and quercetin containing tablets in
the specifications required for this study and Dr. Daniel
Williams for assistance in statistical analysis.
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TABLE 5 Plasma lipid and fasting blood glucose concentrations in prehypertensive and stage
1 hypertensive subjects before and after supplementation with quercetin and placebo
1
Total cholesterol LDL HDL VLDL Triglycerides Glucose
Prehypertensive, n¼19 mmol/L
Placebo
Baseline 5.12 60.24 3.03 60.17 1.24 60.12 0.83 60.11 1.82 60.24 5.68 60.18
Endpoint 5.38 60.22 3.17 60.17 1.31 60.12 0.87 60.10 1.93 60.21 5.89 60.20
Quercetin
Baseline 5.13 60.23 3.00 60.20 1.24 60.13 0.91 60.13 2.00 60.24 5.99 60.25
Endpoint 5.15 60.24 3.04 60.17 1.25 60.11 0.80 60.06 1.76 60.12 5.89 60.14
Stage 1 hypertensive, n¼22
Placebo
Baseline 5.32 60.21 2.98 60.21 1.27 60.08 1.08 60.15 2.37 60.34 6.37 60.28
Endpoint 5.33 60.18 3.09 60.17 1.31 60.09 1.00 60.13 2.20 60.29 6.11 60.18
Quercetin
Baseline 5.34 60.22 3.23 60.24 1.23 60.09 1.05 60.18 2.32 60.39 6.00 60.20
Endpoint 5.22 60.24 3.09 60.26 1.25 60.11 1.10 60.15 2.43 60.34 6.12 60.24
1
Values are means 6SEM. There were no changes in either group during either phase of the study.
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Quercetin reduces blood pressure 2411
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... Another double-blind placebo-controlled study showed that BP was not altered in prehypertensive patients after quercetin supplementation [36]. However, in patients with first stage of hypertension, it was significantly reduced after quercetin treatment [36]. ...
... Another double-blind placebo-controlled study showed that BP was not altered in prehypertensive patients after quercetin supplementation [36]. However, in patients with first stage of hypertension, it was significantly reduced after quercetin treatment [36]. The small population of this study (41 patients) encourages examination of these findings further on larger group of patients. ...
... Available studies on BP reduction were mainly interventional, focusing on quercetin supplementation's impact on hypertension. They generally showed that quercetin supplementation decreased the BP level in hypertensive patients, while such a relation was not observed in prehypertensive (healthy) patients in most of the studies [36,40,45]. BP reduction was observed in patients with other known CVD risk factors (T2D, metabolic syndrome, smoking, or hyperuricemia) [38,40,41,44]. ...
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Cardiovascular disease (CVD) is the leading cause of deaths globally. The main target for prevention of cardiovascular (CV) risk are lifestyle changes, including particular dietary recommendations, involving high intake of fruits and vegetables. Flavonols are a subgroup of flavonoids—compounds present in fruits, vegetables, and tea—known for their antioxidative properties. There are many findings about the beneficial impact of flavonols on general CV risk and its factors, but mainly from in vitro and animal model studies. This paper summarizes data from human studies about flavonols’ impact on general CV risk and its factors. A high dietary intake of flavonols could decrease CVD mortality directly or through impact on selected CV factors; however, available data are inconsistent. Nonetheless, specific groups of patients (smoking men, hypertensive and diabetic patients) can potentially benefit from selected dietary modifications or flavonols (quercetin) supplementation. Future investigations about kaempferol and myricetin are needed.
... In STZ-induced rats, quercetin improved retinopathy by down-regulating matrix metalloproteinase-9 (MMP-9), monocyte chemo-attractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) [128]. In hypercholesterolemic mice, it reduced diabetic nephropathy by lowering triglycerides and blood glucose levels [129]. ...
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Diabetes Mellitus (DM) is a metabolic disorder that is spreading alarmingly around the globe. Type-2 DM (T2DM) is characterized by low-grade inflammation and insulin resistance and is closely linked to obesity. T2DM is mainly controlled by lifestyle/dietary changes and oral antidiabetic drugs but requires insulin in severe cases. Many of the drugs that are currently used to treat DM are costly and present adverse side effects. Several cellular, animal, and clinical studies have provided compelling evidence that flavonoids have therapeutic potential in the management of diabetes and its complications. Quercetin is a flavonoid, present in various natural sources, which has demonstrated in vitro and in vivo antidiabetic properties. It improves oral glucose tolerance, as well as pancreatic β-cell function to secrete insulin. It inhibits the α-glucosidase and DPP-IV enzymes, which prolong the half-life of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Quercetin also suppresses the release of pro-inflammatory markers such as IL-1β, IL-4, IL-6, and TNF-α. Further studies are warranted to elucidate the mode(s) of action of quercetin at the molecular level. This review demonstrates the therapeutic potential of quercetin in the management of T2DM.
... The QQ-GSH complex termed GSQ is unstable and would release QQ in 2 min, and QQ-induced toxicity is further spread in vivo after being transported to remote areas [59]. Nonetheless, quercetin is considered safe, and numerous clinical trials have been carried out on conditions ranging from infectious diseases [60][61][62], tumor [63], and rheumatoid arthritis [64] to hypertension and sarcoidosis [65,66]. ...
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... Other compounds of interest in cardiovascular protection are quercetin and tangeretin. Quercetin exerts favorable effects on hypertension and their potential sources include apples, onions, black tea, and red grapes [204]. Tangeretin, an Opolymethoxylated flavone found in citrus peels, is known to exert antiplatelet activity by inactivating platelet-forming growth factor, which induces the multiplication and alteration of smooth muscles [205,206]. ...
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Polyphenols are abundant micronutrients in our diet, and evidence for their role in the prevention of degenerative diseases is emerging. Bioavailability differs greatly from one polyphenol to another, so that the most abundant polyphenols in our diet are not necessarily those leading to the highest concentrations of active metabolites in target tissues. Mean values for the maximal plasma concentration, the time to reach the maximal plasma concentration, the area under the plasma concentration-time curve, the elimination half-life, and the relative urinary excretion were calculated for 18 major polyphenols. We used data from 97 studies that investigated the kinetics and extent of polyphenol absorption among adults, after ingestion of a single dose of polyphenol provided as pure compound, plant extract, or whole food/beverage. The metabolites present in blood, resulting from digestive and hepatic activity, usually differ from the native compounds. The nature of the known metabolites is described when data are available. The plasma concentrations of total metabolites ranged from 0 to 4 mumol/L with an intake of 50 mg aglycone equivalents, and the relative urinary excretion ranged from 0.3% to 43% of the ingested dose, depending on the polyphenol. Gallic acid and isoflavones are the most well-absorbed polyphenols, followed by catechins, flavanones, and quercetin glucosides, but with different kinetics. The least well-absorbed polyphenols are the proanthocyanidins, the galloylated tea catechins, and the anthocyanins. Data are still too limited for assessment of hydroxycinnamic acids and other polyphenols. These data may be useful for the design and interpretation of intervention studies investigating the health effects of polyphenols.
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Background: Epidemiological studies suggested that consumption of fruit and vegetables may protect against stroke. The hypothesis that dietary antioxidant vitamins and flavonoids account for this observation is investigated in a prospective study. Methods: A cohort of 552 men aged 50 to 69 years was examined in 1970 and followed up for 15 years. Mean nutrient and food intake was calculated from crosscheck dietary histories taken in 1960, 1965, and 1970. The association between antioxidants, selected foods, and stroke incidence was assessed by Cox proportional hazards regression analysis. Adjustment was made for confounding by age, systolic blood pressure, serum cholesterol, cigarette smoking, energy intake, and consumption of fish and alcohol. Results: Forty-two cases of first fatal or nonfatal stroke were documented Dietary flavonoids (mainly quercetin) were inversely associated with stroke incidence after adjustment for potential confounders, including antioxidant vitamins. The relative risk (RR) of the highest vs the lowest quartile of flavonoid intake (greater than or equal to 28.6 mg/d vs <18.3 mg/d) was 0.27 (95% confidence interval [CI], 0.11 to 0.70). A lower stroke risk was also observed for the highest quartile of beta-carotene intake (RR, 0.54; 95% CI, 0.22 to 1.33). The intake of vitamin C and vitamin E was not associated with stroke risk. Black tea contributed about 70% to flavonoid intake. The RR for a daily consumption of 4.7 cups or more of tea vs less than 2.6 cups of tea was 0.31 (95% CI, 0.12 to 0.84). Conclusions: The habitual intake of flavonoids and their major source (tea) may protect against stroke.
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Accuracy of computerized nutrient databases is an important consideration in selecting a nutrient analysis system. We project compared the nutrient content of daily menus calculated from 4 microcomputer programs to chemical analysis of menus analyzed for the Dietary Approaches to Stop Hypertension (DASH) trial. Thirty-six menus were entered at 2 independent DASH sites using the ESHA Food Processor, Minnesota Nutrition Data System, Moore's Extended Nutrient Database, and Nutritionist IV databases. Food prepared according to these menus was chemically analyzed at the Food Analysis Laboratory Control Center at Virginia Polytechnic Institute and State University, Department of Biochemistry, Blacksburg. Estimates for 13 nutrients were compared: energy, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, carbohydrate, protein, cholesterol, calcium, potassium, magnesium, iron, and sodium. The overall intraclass correlation between the 2 sites’ data entry was 0.998; thus, values were averaged for analyses. Databases varied significantly in their mean deviations from chemical analyses values for saturated, monounsaturated, and polyunsaturated fatty acids, potassium, magnesium, and iron (P
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Background. The Cholestech L·D·X analyzer has the capability of performing a lipid profile in approximately 5 minutes. The purpose of this study was to determine analytical performance capability of the L·D·X to perform lipid profile measurements. Methods. Forty subjects gave two finger capillary samples and one venous serum which were analyzed in duplicate by two technicians, on two different L·D·X analyzers. A local pathology laboratory was used as the standard for accuracy comparisons. Two controls with known values were provided by the manufacturer to assess within-day precision. Day-to-day precision was determined by analyzing high (240 mg/dL-1 total cholesterol (TC) and 60 mg/dL-1 high-density lipoprotein [HDL]) and low (200 mg/dL-1 TC and 35 mg/dL-1 HDL) human serum samples on 10 different days. Results. Analysis of variance procedures revealed no significant differences between the two technicians or the two analyzers, nor among the fingerstick, venous serum, or reference measures for any of the analytes. The total error of measurement of TC, triglycerides, and HDL measurements were 6.3 to 16.2%, 14.8 to 30.8%, and 11.5 to 26.8%, respectively. In comparison to the National Cholesterol Education Program (NCEP) desirable, borderline-high, and high classifications obtained from the reference laboratory the L·D·X TC results were correctly classified in 92.5% of the cases. L·D·X triglyceride classifications of desirable, borderline hypertyglyceridemia, and distinct hypertriglyceridemia matched 100% with the classifications obtained from the reference laboratory. Conclusions. Although the Cholestech L·D·X analyzer did not consistently meet NCEP standards for acceptable total measurement error of TC, HDL, and triglyceride analyses, it seems capable of providing reasonable lipid profile measures in both a screening setting and a clinician office where the goal is correct classification of patients' results.
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The effects of an oral daily dose (10 mg kg−1) of the flavonoid quercetin for 5 weeks in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) were analysed. Quercetin induced a significant reduction in systolic (−18%), diastolic (−23%) and mean (−21%) arterial blood pressure and heart rate (−12%) in SHR but not in WKY rats. The left ventricular weight index and the kidney weight index in vehicle-treated SHR were significantly greater than in control WKY and these parameters were significantly reduced in quercetin-treated SHR in parallel with the reduction in systolic blood pressure. Quercetin had no effect on the vasodilator responses to sodium nitroprusside or to the vasoconstrictor responses to noradrenaline or KCl but enhanced the endothelium-dependent relaxation to acetylcholine (Emax=58±5%vs 78±5%, P<0.01) in isolated aortae. The 24 h urinary isoprostane F2α excretion and the plasma malonyldialdehyde (MDA) levels in SHR rats were increased as compared to WKY rats. However, in quercetin-treated SHR rats both parameters were similar to those of vehicle-treated WKY. These data demonstrate that quercetin reduces the elevated blood pressure, the cardiac and renal hypertrophy and the functional vascular changes in SHR rats without effect on WKY. These effects were associated with a reduced oxidant status due to the antioxidant properties of the drug. British Journal of Pharmacology (2001) 133, 117–124; doi:10.1038/sj.bjp.0704064