Bioscience, Biotechnology, and Biochemistry

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Antihypertensive Effect of Quercetin in Rats Fed

with a High-Fat High-Sucrose Diet
Yukiko YAMAMOTO & Eriko OUE
To cite this article: Yukiko YAMAMOTO & Eriko OUE (2006) Antihypertensive Effect of Quercetin
in Rats Fed with a High-Fat High-Sucrose Diet, Bioscience, Biotechnology, and Biochemistry,
70:4, 933-939, DOI: 10.1271/bbb.70.933
To link to this article: http://dx.doi.org/10.1271/bbb.70.933

Published online: 22 May 2014.

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Date: 17 September 2016, At: 14:41

Biosci. Biotechnol. Biochem., 70 (4), 933939, 2006

Antihypertensive Eect of Quercetin in Rats Fed with a High-Fat

High-Sucrose Diet
Yukiko YAMAMOTO1; y and Eriko O UE2
1

Graduate School of Human Life Science, Osaka City University, Sugimoto 3-3-138, Sumiyoshi-ku,
Osaka 558-8585, Japan
2
Faculty of Human Life Science, Osaka City University, Sugimoto 3-3-138, Sumiyoshi-ku, Osaka 558-8585, Japan
Received September 29, 2005; Accepted December 10, 2005

The eects of dierent levels of quercetin on the

blood pressure were studied in 6-week-old male Sprague-Dawley rats. The rats were fed with a control diet or
a high-fat high-sucrose (HFS) diet containing 0, 0.02,
0.07, 0.2, or 0.5% quercetin for 4 weeks. The systolic
blood pressure and the lipid peroxides in the plasma
were both higher in the rats fed with the HFS diet
without quercetin than in the rats fed with the control
diet. The nitric oxide synthase (NOS) activity in the
vascular tissues and nitric oxide (NO) metabolites in the
plasma and urine were both lower in these rats. A
distinct depression of the increase in blood pressure was
found in the rats fed with the HFS diets containing
quercetin. Each level of quercetin examined was eective, the 0.5% level being much more eective than
other levels. Dietary quercetin decreased lipid peroxidation in the plasma of the rats fed with the HFS diets.
Quercetin also suppressed the decrease in NO metabolites in the plasma and urine, and the NOS activity in
the vascular tissues of these rats. These results suggest
that the increased NO availability caused by the
elevated NOS activity, and the antioxidative activity in
these rats fed with quercetin may be sources of the
antihypertensive eect of quercetin.
Key words:

quercetin; high-fat high-sucrose diet; hypertension; NO synthase activity; antioxidative

activity

It is well known that a diet high in saturated fat and

rened-carbohydrate (sucrose) leads to hyperlipidemia
and hypercholesterolemia, and increases the risk of
cardiovascular disease. Several recent studies have
shown that the consumption of a high-fat or high-fat
high-sucrose (HFS) diet induced a signicant rise in the
arterial blood pressure of normotensive rats.13) The
hypertensive eects of the HFS diet were accompanied
by oxidative stress,1,3) but the role of oxidative stress in
the genesis and maintenance of hypertension is not yet
fully understood. This type of hypertension is a model
for life-style related disease, and another type of
y

hypertension is the spontaneously hypertensive rat

(SHR), this being a model for essential hypertension.
In the case of SHR, the importance of oxidative stress on
the development of hypertension was evident from
experiments involving the administration of many kinds
of antioxidant48) with consequent lowering of the
hypertension.
The endothelium-derived relaxing factor, nitric oxide
(NO), is produced from arginine by NO synthase (NOS)
activity, and is responsible for acetylcholine-mediated
vascular relaxation. Several recent studies have suggested a link between high-fat mediated oxidative stress and
decreased NOS activity in hyperlipidemic animals9,10)
and isolated rat hepatocytes.11) These results suggest that
the reduced NOS activity and subsequent decreased NO
concentration might lead to an elevated blood pressure.
Quercetin is the most abundant of the avonol-type
avonoids in fruits and vegetables. A wide range of
biological actions of quercetin, including vasodilation
and antithrombotic eects, has been reported.12,13) The
eects of quercetin on blood pressure have been studied
less extensively. We have found only one report on the
antihypertensive eects of quercetin on SHR,14) but
details of this eect were not presented. Furthermore, no
such report has been found on normotensive rats.
Quercetin is also well known to have in vitro15,16) and
in vivo17,18) antioxidative eects. However, we have not
found any information on the eects of quercetin on the
NOS activity in vascular tissues of rats fed with an HFS
diet.
Our present work examines the eects of dietary
quercetin added at various levels (0.02, 0.07, 0.2 or
0.5%) on the hypertensive status of rats fed with an HFS
diet to elucidate the eect of quercetin on life-stylerelated hypertension. The eects of quercetin on the
oxidative status and NOS activity are also reported.

Materials and Methods

Animals and experimental diet. Forty-nine 6-week-old
male Sprague-Dawley rats were obtained from SLC

To whom correspondence should be addressed. Fax: +81-6-6605-2819; E-mail: Yamamoto@life.osaka-cu.ac.jp

934

Y. YAMAMOTO and E. OUE

Japan (Hamamatsu, Japan), and were separated into two

groups of 21 and 28 rats each for experiments 1 and 2,
respectively. The animals were housed individually in
cages with wire mesh bottoms in a room kept at 22

1  C and with a 12:12-h light:dark cycle (a light period
from 8:00 to 20:00 h). The animals were given free
access to water and a basal diet for the rst 4 or 5 days,
and were subsequently randomly divided into test
groups of seven animals each with similar average
values for the initial body weight and systolic blood
pressure. In experiment 1, one group received a control
diet (Control group), and the other two groups were fed
with a high-fat high-sucrose (HFS) diet containing none
or 0.2% of quercetin (HFS and 0.2Q groups). In
experiment 2, four groups were fed with an HFS diet
containing none, 0.02, 0.07, or 0.5% of quercetin (HFS,
0.02Q, 0.07Q, and 0.5Q groups). The composition of the
basal diet was as follows (wt %): corn oil, 5.0; mineral
mixture, 3.5; vitamin mixture, 1.0; choline bitartrate,
0.25; casein, 20.0; cellulose, 5.0; and corn
-starch to
make 100. The composition of the HFS diet was as
follows (wt %): corn oil, 5.0; lard, 15.0; cholesterol, 0.5;
mineral mixture, 3.5; vitamin mixture, 1.0; choline
bitartrate, 0.25; casein, 20.0; sucrose, 40.0; cellulose,
5.0; and corn
-starch to make 100. The composition of
the quercetin diet was similar to the HFS diet, except
that 0.02, 0.07, 0.2, or 0.5% of the cellulose was
replaced with quercetin. Quercetin was purchased from
Wako Pure Chemicals Co., Ltd. (Osaka, Japan). The
composition of the mineral mixture was AIN-93G-MX
and that of the vitamin mixture was AIN-93-VX.19) Food
and water were given ad libitum for the 4-week duration
of the experiment. All experiments were done under the
Ethics Guidelines for Animal Experiments of Osaka
City University.
Sampling procedures. After the 4-week growing
period, the rats were starved overnight, anesthetized,
and their blood was collected in a heparinized syringe
from the abdominal aorta. The plasma was separated by
centrifugation at 1;000  g and 4  C for 15 min. A
portion of the plasma was used to measure the lipid
peroxide, and the rest was stored at 80  C while
awaiting a biochemical analysis. Immediately after
blood sampling, the thoracic aorta was taken out, rinsed
gently with chilled saline, blotted, and stored at 80  C
while awaiting an analysis of the nitric oxide synthase
(NOS) activity. Urine was collected during the last 3
days of the growing period with the rats placed in
stainless steel metabolic cages.
Blood pressure. The systolic blood pressure was
measured at the start and at the end of the 2- and 4-week
feeding periods by the tail-cu method20) with a BP98
instrument (Softron, Japan).
Lipid concentration in the plasma. The concentrations
of total cholesterol and triacylglycerol in the plasma

were determined by enzymatic colorimetric tests with

commercial diagnostic kits (cholesterol CII-test and
triglyceride G-test, respectively) from Wako Pure
Chemicals.
Lipid peroxides in the plasma. Lipid peroxides in the
blood plasma were measured as thiobarbituric acid
reactive substances (TBARS) by the spectrometric
method21) and are expressed as the amount of malondialdehyde (MDA) in the plasma.
Nitric oxide (NO) metabolites in the urine and
plasma. The total nitrate and nitrite concentrations in
the urine and plasma were measured by reacting with the
Greiss reagent according to the procedure described by
Wu et al.22) The NO metabolites excreted in the urine
are expressed as total nitrate and nitrite per creatinine in
the urine. Creatinine excreted in the urine was determined by using a commercial diagnostic kit (creatininetest) from Wako Pure Chemicals.
NOS activity in the aorta. NOS activity was measured
by the method of Bredt and Snyder.23) The abdominal
aorta were homogenized with ve volumes of 50 mM
HEPES (pH 7.4) containing 1 mM dithiothreitol, 1 mM
EDTA, 5 mg/ml of phenylmethylsulphonyl uoride, 5
mg/ml of pepstatin and 5 mg/ml of aprotinine. The
homogenate was centrifuged for 5 min at 11;000  g,
and the resulting supernatant was used for the NOS
assays. The assay mixture consisted of 12.5 mM HEPES
(pH 7.3), 1.2 mM MgCl2 , 0.96 mM CaCl2 , 3 mM tetrahydrobiopterin, 1 mM FAD, 1 mM FMN, 0.024 mM Larginine, 0.01 mmol L-[U-14 C]arginine (1.5 kBq), 0.12
mM NADPH, and 0.02 ml of the homogenate supernatant in a nal volume of 0.1 ml. The NOS activity is
expressed as the amount of citrulline produced per
protein. Protein was determined by the method of Lowry
et al.24)
Statistical analysis. Each data value for the animal
experiments is expressed as the mean
SEM of seven
rats. Data were subjected to an analysis of variance (oneway ANOVA) and multiple-range comparison by Fishers protected least signicant dierence (PLSD) procedure by using StatView (Abacus Concepts, Berkeley,
CA, USA). A P value of <0:05 is considered signicantly dierent.

Results
Growth, dietary intake, and lipids in the plasma
In experiment 1, the body weight gain and food
eciency in the HFS group were higher than those of
the control group (Table 1, experiment 1). The body
weight gain and food intake of the 0.2Q group were no
dierent from those of the HFS group, but the food
eciency of the 0.2Q group was lower than that of the
HFS group. The epididymal fat weight and total

Antihypertensive Eect of Quercetin

935

Table 1. Eects of Dietary Quercetin on the Growth, Dietary Intake, and Lipids in the Plasma from Rats Fed with the High-Fat High-Sucrose Diets
for 4 Weeks
Experiment 1
Control

HFS

b*

Experiment 2
0.2Q

HFS
a*

0.02Q

0.07Q

0.5Q

Body weight gain (g/4 weeks)

Food intake (g/4 weeks)
Food eciency (%)
Epididymal fat weight (g)

156
6
535
10a
29:0
1:7c
4:42
0:43b

186
5
503
9ab
36:9
1:7a
6:60
0:35a

168
9
487
14b
34:3
2:9b
6:46
0:48a

179
8
508
15
35:2
0:7ab
7:53
0:64a

182
7
505
13
36:0
0:7a
7:96
0:59a

179
6
504
8
35:5
0:8ab
7:40
0:60a

156
7b
473
14
33:0
1:0b
5:27
0:19b

Lipids in plasma
Total cholesterol (mmol/l)
Triacylglycerol (mmol/l)

1:40
0:04b
1:89
0:07a

1:93
0:05a
1:67
0:10ab

1:87
0:07a
1:59
0:08b

1:89
0:08
1:72
0:15

1:88
0:11
1:79
0:10

1:80
0:07
1:75
0:07

1:82
0:08
1:70
0:07

ab

Mean
SEM, n 7. Values within a row with dierent superscript letters in each experiment are signicantly dierent from each other (p < 0:05).
(Body weight gain/food intake)  100.



Table 2. Eects of Dietary Quercetin on the Systolic Blood Pressure of Rats Fed with the High-Fat High-Sucrose Diets for 4 Weeks
Experiment 1

0 week
2 weeks
4 weeks


Experiment 2

Control

HFS

0.2Q

HFS
(mm Hg)

0.02Q

0.07Q

0.5Q

120
2
123
2b
126
2c

121
1
143
3a
151
2a

122
2
133
4b
136
1b

123
3
149
2a
154
2a

124
2
143
1b
143
2b

121
1
143
4b
141
2b

123
2
137
3b
135
2c

Mean
SEM, n 7. Values within a row with dierent superscript letters in each experiment are signicantly dierent from each other (p < 0:05).

Systolic blood pressure

The systolic blood pressure of the rats in the HFS
group was higher than that in the control group at 2 and
4 weeks, and the pressure of the rats in the 0.2Q group
was lower than that in the HFS group at 2 and 4 weeks
(Table 2, experiment 1). The systolic blood pressure
of the rats in the 0.02Q, 0.07Q, and 0.5Q groups was
lower than that in the HFS group at 2 and 4 weeks. The
eect on the 0.5Q group of suppressing the increase in
blood pressure was stronger than that on the 0.02Q and
0.07Q groups at 4 weeks (Table 2, experiment 2). As
shown in Fig. 1, quercetin added to the diet was
concentration-dependently eective for suppressing the
increase in blood pressure of the rats fed with the highfat high-sucrose diet.

Decrease in
systolic blood pressure
(mm Hg)

cholesterol in the plasma from the HFS and 0.2Q groups

were higher than those from the control group, the
gures for the 0.2Q group being no dierent from the
HFS group. Triacylglycerol in the plasma from the 0.2Q
group was no dierent from that from the HFS group. In
experiment 2, the body weight gain of the 0.5Q group
was lower than that of the HFS, 0.02Q, and 0.07Q
groups (Table 1, experiment 2). The food intake and
food eciency of the 0.02Q, 0.07Q, and 0.5Q groups
were no dierent from those of the HFS group. The
epididymal fat weight of the 0.5Q group was lower than
that of the HFS, 0.02Q, and 0.07Q groups. Total
cholesterol and triacylglycerol in the plasma from these
four groups were no dierent from each other.

-5
-10
-15
-20
-25
-30
0

0.1

0.2

0.3

0.4

0.5

Quercetin in diet
(%)
Fig. 1. Concentration-Dependent Eects of Quercetin on the Systolic
Blood Pressure in Rats Fed with the High-Fat High-Sucrose Diets.
The decrease in blood pressure from the HFS group (calculated
from the data at 4 weeks in Table 1) is plotted against the dietary
quercetin concentration.

NO metabolites in the plasma and urine

In respect of the plasma, the concentration of NO
metabolites in the HFS group was signicantly lower
than that in the control group, and the value in the 0.2Q
group was similar to that in the control group (Fig. 2,
experiment 1). This concentration in the 0.02Q and
0.07Q groups was signicantly higher than that in the
HFS group, the value in the 0.5Q group being higher
than that in the 0.02Q and 0.07Q groups (Fig. 2,
experiment 2).
In respect of the urine, the excreted amount of NO
metabolites in the HFS group was signicantly lower
than that in the control group, the value in the 0.2Q

936

Y. YAMAMOTO and E. OUE

120

120

(Exp. 1)

(Exp. 2)
100

80
a

60
b
40

Plasma NO2-/NO3(mol/l)

Plasma NO2-/NO3(mol/l)

100

a
80
b

60
c
40
20

20

0
Control

HFS

0.2Q

HFS

0.02Q

0.07Q

0.5Q

Fig. 2. Eects of Dietary Quercetin on NO Metabolites in the Plasma from Rats Fed with the High-Fat High-Sucrose Diets.
Values with dierent letters in each experiment are signicantly dierent from each other (p < 0:05).

(Exp. 2)

2.5
2

1.5
b
1
0.5

Urinary NO2-/NO3(mol/mmol creatinine)

Urinary NO2-/NO3(mol/mmol creatinine)

(Exp. 1)
2.5
2
1.5
1

Control

HFS

0.2Q

0.5
0

HFS

0.02Q

0.07Q

0.5Q

Fig. 3. Eects of Dietary Quercetin on NO Metabolites Excreted in the Urine by Rats Fed with the High-Fat High-Sucrose Diets.
Values with dierent letters in each experiment are signicantly dierent from each other (p < 0:05).

group being similar to that in the control group (Fig. 3,

experiment 1). The values in the 0.02Q and 0.07Q
groups were signicantly higher than that in the HFS
group, while the value in the 0.5Q group was higher
than that in the 0.02Q and 0.07Q groups (Fig. 3,
experiment 2).
NOS activity in the aorta
The NOS activity in the aorta of the HFS group was
signicantly lower than that of the control group, this
activity of the 0.2Q group being higher, but not
signicantly, than that of the HFS group (Fig. 4,
experiment 1). The activity of the 0.02Q and 0.07Q
groups was higher, but not signicantly, than that of the
HFS group, the value for the 0.5Q group being
signicantly higher than that for the HFS, 0.02Q and
0.07Q groups (Fig. 4, experiment 2).
Lipid peroxides in the plasma
In experiment 1, the TBARS value in the plasma was
higher in the rats of the HFS group than of the control
group, and the value for the 0.2Q group was lower than
that for the HFS group (Fig. 5). In experiment 2, the
TBARS value in the plasma from the 0.5Q group, but
not that from the 0.02Q or 0.07Q group, was signicantly lower than that from the HFS group.

Discussion
Current interest in health foods has spurred studies on
the hypolipidemic and hypocholesterolemic eects of
food components. Quercetin and other avonoids have
been shown to inhibit cholesterol biosynthesis in hepatic
cells.25) The inhibitory eects of quercetin on fatty acid
synthase activity have also been shown in an in vitro
experiment.26) In this present experiment, no eect of
quercetin on decreasing triacylglycerol and cholesterol
in the plasma was apparent in the rats fed with the highfat high-sucrose diet. These results suggest that quercetin had no signicant hypolipidemic eect when added
to the diet at a concentration of less than 0.5%.
Although a wide range of biological eects of
quercetin has been reported in previous studies, only a
few reports were found on the antihypertensive eects
of quercetin. Duarte et al. have shown antihypertensive
eects of quercetin on SHR by orally dosing,14) but no
report was found on normotensive rats. In the present
experiment, we found that quercetin suppressed the
increase in blood pressure and lipid peroxidation in
normotensive rats fed with the high-fat high-sucrose
diets. The eective dietary levels of quercetin were 0.02,
0.07, 0.2, and 0.5%, the level of 0.5% being much more
eective than the other levels.

Antihypertensive Eect of Quercetin

0.4

0.5

(Exp. 1)
a

0.3
b

0.2
b
0.1

Control

HFS

(Exp. 2)

NO synthase activity in aorta

(pmol/min/mg of protein)

NO synthase activity in aorta

(pmol/min/mg of protein)

0.5

937

0.4
a
0.3
b

0.02Q

0.07Q

0.2
b
0.1

0.2Q

HFS

0.5Q

Fig. 4. Eects of Dietary Quercetin on the NOS Activity in Vascular Tissues of Rats Fed with the High-Fat High-Sucrose Diets.
Values with dierent letters in each experiment are signicantly dierent from each other (p < 0:05).
8.0

8.0

7.0
6.0

5.0
b

4.0
c
3.0
2.0
1.0
0.0
Control

HFS

0.2Q

Plasma TBARS (nmol/ml)

Plasma TBARS (nmol/ml)

(Exp. 1)

(Exp. 2)

7.0
6.0

5.0
ab
4.0

ab
b

3.0
2.0
1.0
0.0
HFS

0.02Q

0.07Q

0.5Q

Fig. 5. Eects of Dietary Quercetin on TBARS in the Plasma from Rats Fed with the High-Fat High-Sucrose Diets.
Values with dierent letters in each experiment are signicantly dierent from each other (p < 0:05).

A signicant rise in blood pressure was accompanied

with enhanced oxidation in the rats fed with the high-fat
high-sucrose diet. These results suggest a probable role
of oxidative stress on the genesis and maintenance of
hypertension. Oxidative stress may contribute to hypertension via several mechanisms. Superoxide is known
to react quickly with NO,27) and its consequent deactivation of NO is responsible for the retardation of
acetylcholine-mediated vascular relaxation. In this present experiment, the operation of such a mechanism is
supported by the results that the level of NO metabolites
in the plasma and urine was signicantly lower in the
rats fed with the high-fat high-sucrose diet. Furthermore,
we suggest that the development of increased blood
pressure in these rats was attributable to the reduced
NOS activity and then to decreased NO production. The
observed decrease in the NOS activity in vascular tissues
suggests a possible endothelial dysfunction in the rats
fed with a high-fat high-sucrose diet. These results are
similar to other recent ndings; the protein expression of
endothelial NOS (eNOS) was lower in hyperlipidemic
rats,9) hypercholesterolemic pigs,10) and cells exposed to
triacylglycerol-mediated oxidative stress.11)
In respect of the eect of avonoids, we showed that
quercetin was eective for depressing lipid peroxidation
and suppressing the decrease in NO metabolites in the
plasma and urine of rats fed with a high-fat high-sucrose

diet. These results suggest the possibility that the eect

of quercetin on suppressing the elevation of blood
pressure might have come from an increase in NO
availability due to its antioxidative activity. Furthermore, we showed that quercetin was eective for
increasing the NOS activity in the vascular tissues of
rats fed with a high-fat high-sucrose diet. These results
suggest that another cause of the eect of quercetin on
suppressing the elevation of blood pressure might have
come from the increased NOS activity and subsequent
suppression of the decrease in NO production in these
rats. Several reports have recently suggested that
antioxidative vitamins were eective for protecting
NOS activity by preventing the NOS protein modulation
from oxidation10) and by preventing the depletion of
NOS cofactor tetrahydrobiopterin (BH4 ).28) BH4 is a
tightly bound cofactor of NOS, and the absence of BH4
is known to lead to uncoupling of the L-arginine-NO
pathway and then causing superoxide formation instead
of NO formation.29) Although we did not identify the
precise mechanism whereby quercetin prevented the
decrease in NOS activity in the vascular tissues in this
experiment, the possibility that the antioxidative activity
of quercetin might be eective for protecting the NOS
protein and its cofactor BH4 from oxidative stress could
be assumed.
The vasoconstrictor, angiotensin II, is also important

938

Y. YAMAMOTO and E. OUE

in blood pressure control, and the eect of quercetin on

decreasing angiotensin II production is another possible
mechanism for suppressing the elevation of blood
pressure. A recent study has demonstrated enhanced
angiotensinogen gene expression in adipose tissue and a
high concentration of angiotensin II in the plasma of rats
and mice.30,31) These results suggest that adiposederived angiotensinogen could contribute to plasma
angiotensin II, and then to blood pressure. Although we
have not been able to nd any reports showing the
suppression of angiotensin II production by quercetin,
the signicant decrease in the weight of adipose tissue
may have caused the suppressed angiotensin II prodution in the rats fed with the diet containing 0.5%
quercetin. Furthermore, we cannot exclude the possibility that quercetin might be a potent angiotensinconverting enzyme inhibitor. Further studies are needed
to elucidate whether quercetin would be eective for
suppressing angiotensin II production.
In summary, we have demonstrated that quercetin
suppressed the elevation of blood pressure in normotensive rats fed with the high-fat high-sucrose diets. The
eective dietary levels of quercetin were 0.02, 0.07, 0.2,
and 0.5%, the level of 0.5% being much more eective
than the other levels. The increased NO availability
caused by the elevated NOS activity, and the antioxidative activity, in the rats fed with quercetin is
suggested to be one of the causes of the suppressed
elevation of blood pressure.

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