A Red Wine Vinegar Beverage can Inhibit the Renin-Angiotensin System: Experimental Evidence in Vivo

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DOI: 10.1248/bpb.28.1208 · Source: PubMed
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Abstract
A new beverage made of red wine vinegar and grape juice (Budo-no-megumi) was developed for people who wish to take effective amount of both polyphenols and vinegar. Since the beverage was recently demonstrated to exert hypotensive effect in rats, we analyzed its underlying mechanisms in this study. Sprague-Dawley rats were anesthetized with pentobarbital, and the blood pressure and lead II ECG were continuously monitored (n=6). The effects of recommended volume of the beverage (3 ml/kg, p.o.) on the renin-angiotensin system were assessed in vivo. At the basal control state, the increase in the mean blood pressure induced by the angiotensin I (1 microg/kg, i.v.) and norepinephrine (0.3-3 microg/kg, i.v.) were +57+/-2 and +36+/-8 mmHg, respectively. Sixty minutes after the administration of the beverage, the angiotensin I-induced pressor response decreased to +45+/-7 mmHg at 60 min (p<0.05), whereas no significant change was detected in the norepinephrine-induced pressor response. In another parallel series of the experiment using Sprague-Dawley rats (n=6), the serum angiotensin-converting enzyme activity was 39.4+/-1.2 IU/l at basal control state, which was slightly but significantly decreased to 37.0+/-1.4 IU/l at 60 min after the administration of the beverage (p<0.01). These results suggest that previously described hypotensive action of the beverage may be partly induced by the inhibition of angiotensin-converting enzyme.
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Since hypertension is one of the major independent risk
factors for arteriosclerosis, stroke, myocardial infarction and
end-stage renal disease, attempts have been extensively made
in the field of food science and technology to discover food-
stuffs that may improve the self-regulating mechanism of the
blood pressure levels.
1,2)
A new beverage made of red wine
vinegar and grape juice (Budo-no-megumi
TM
) was developed
for people who wish to get enough grape polyphenols and
vinegar for their health. A recent study has indicated that a
single oral administration of the beverage (3 ml/kg) decreases
the blood pressure and heart rate of the pentobarbital-anes-
thetized rats.
3)
Since information regarding the mechanism of
hypotensive action of the beverage is still limited,
4)
we ana-
lyzed the in vivo effects of the beverage on the renin-an-
giotensin system in this study.
MATERIALS AND METHODS
Animals were obtained through Animal Laboratory for
Research of University of Yamanashi. All experiments were
performed in accordance with Guidelines for Animal Experi-
ments of University of Yamanashi.
Effects on the Angiotensin I-Induced and Norepineph-
rine-Induced Pressor Responses Male Sprague-Dawley
rats weighing 200—300 g were anesthetized with 50 mg/kg
of intra-peritoneal injection of pentobarbital sodium. After a
tracheal cannula was inserted, the animals were artificially
ventilated with room air (Shinano, SN-480-7, Tokyo, Japan).
The tidal volume and respiratory rate were set at 10 ml/kg
and 60 strokes/min, respectively. The right femoral artery and
vein were cannulated with heparinized catheters for the blood
pressure measurement and the drug administration, respec-
tively. The surface lead II electrocardiogram (ECG) was ob-
tained from the limb electrodes. The ECG and systemic
blood pressure were continuously monitored using a poly-
graph system (Nihon-Kohden, RM-6200, Tokyo, Japan) and
analyzed with a real time full automatic data analysis system
(MP/VAS 3 for Macintosh, Physio-Tech, Tokyo, Japan).
After confirming the stability of the cardiovascular variables,
angiotensin I (1
m
g/kg) and norepinephrine (0.3—3
m
g/kg)
were intravenously injected with a recovery interval of
5 min, and the increase in the mean blood pressure were as-
sessed. After confirming the reproducibility of each pressor
response, a recommended dose of the beverage (3 ml/kg,
n6) or distilled water (3 ml/kg, n6) was administered di-
rectly into the stomach via a gastric tube, whereas a clinically
available angiotensin I-converting enzyme (ACE) inhibitor
temocapril hydrochloride (0.04 mg/kg, n6) was intra-
venously injected. Then, the same doses of angiotensin I and
norepinephrine were injected 60 min after the administration
of the beverage and distilled water, whereas those were done
10 min after the administration of temocapril, based on the
previous report.
3)
Effects on the Serum ACE Activity In another parallel
series of the experiment using male Sprague-Dawley rats
weighing 170—240 g, the effects of the beverage and temo-
capril on the serum ACE activity were analyzed. Under anes-
thesia with ether inhalation, blood was collected from the
jugular vein before and 60 min after the administration of the
beverage (3 ml/kg, p.o., n6), whereas that was performed
before and 10 min after the injection of temocapril
(0.04 mg/kg, i.v., n6), respectively. The serum ACE activity
was assayed with the method by Kasahara and Ashihara.
5)
Subjects and Drugs The beverage made of red wine
vinegar and grape juice (Budo-no-megumi
TM
) was gener-
ously provided by Asaya Foods Co., Ltd. (Yamanashi, Japan).
The beverage consists of 25% (v/v) of red wine vinegar con-
taining 4.5% acetic acid, 5% (w/v) of originally manufac-
1208 Biol. Pharm. Bull. 28(7) 1208—1210 (2005) Vol. 28, No. 7
To whom correspondence should be addressed. e-mail: atsushis@yamanashi.ac.jp © 2005 Pharmaceutical Society of Japan
A Red Wine Vinegar Beverage can Inhibit the Renin-Angiotensin System:
Experimental Evidence in Vivo
Sachiko HONSHO, Atsushi SUGIYAMA,* Akira TAKAHARA, Yoshioki SATO H, Yuji NAKAMURA, and
Keitaro H
ASHIMOTO
Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi;
Tamaho-cho, Nakakoma-gun, Yamanashi 409–3898, Japan.
Received March 16, 2005, accepted April 18, 2005; published online April 22, 2005
A new beverage made of red wine vinegar and grape juice (Budo-no-megumi
TM
) was developed for people
who wish to take effective amount of both polyphenols and vinegar. Since the beverage was recently demon-
strated to exert hypotensive effect in rats, we analyzed its underlying mechanisms in this study. Sprague-Dawley
rats were anesthetized with pentobarbital, and the blood pressure and lead II ECG were continuously monitored
(n6). The effects of recommended volume of the beverage (3 ml/kg, p.o.) on the renin-angiotensin system were
assessed in vivo. At the basal control state, the increase in the mean blood pressure induced by the angiotensin I
(1
mm
g/kg, i.v.) and norepinephrine (0.3—3
mm
g/kg, i.v.) were 572 and 368 mmHg, respectively. Sixty minutes
after the administration of the beverage, the angiotensin I-induced pressor response decreased to 457 mmHg
at 60 min ( p0.05), whereas no significant change was detected in the norepinephrine-induced pressor response.
In another parallel series of the experiment using Sprague-Dawley rats (n6), the serum angiotensin-converting
enzyme activity was 39.41.2 IU/l at basal control state, which was slightly but significantly decreased to
37.01.4 IU/l at 60 min after the administration of the beverage (p0.01). These results suggest that previously
described hypotensive action of the beverage may be partly induced by the inhibition of angiotensin-converting
enzyme.
Key words grape; polyphenol; vinegar; hypotensive effect; angiotensin I-converting enzyme
tured 100% grape juice, and appropriate amount of honey,
oligosaccharides, vitamin C, citrate, glucose and calcium lac-
tate. The beverage has been shown to contain 1.5 mg/ml of
polyphenols as gallic acid units.
3)
Pentobarbital sodium
(Tokyo Kasei, Tokyo, Japan), heparin calcium (Mitsui,
Tokyo, Japan), angiotensin I (Peptide Institute, Osaka,
Japan), norepinephrine (Sigma, St. Louis, MO, U.S.A.) and
temocapril hydrochloride (Sankyo, Tokyo, Japan) were pur-
chased.
Statistics The data are presented as the meanS.E. The
statistical comparisons of mean values within a group were
performed using paired t-test, whereas those between the
groups were assessed using unpaired t-test or one-way, facto-
rial ANOVA. A p-value less than 0.05 was considered signifi-
cant.
RESULTS
Effects on the Angiotensin I-Induced or Norepineph-
rine-Induced Pressor Responses The basal heart rate and
mean blood pressure values were 28338 beats/min and
917 mmHg in the beverage group, 37832 beats/min and
1125 mmHg in the distilled water group, and 327
25 beats/min and 997 mmHg in the temocapril group, re-
spectively. No significant difference was detected in the re-
spective basal control values between the groups. The heart
rate and mean blood pressure values of each group tended to
decrease during the experimental period, but they did not
achieve the statistical significance.
The effects of the beverage, distilled water and temocapril
on the angiotensin I- and norepinephrine-induced pressor re-
sponses are summarized in Fig. 1. The control pressor re-
sponses by the angiotensin I and norepinephrine were
572 and368 mmHg in the beverage group, 543
and 424 mmHg in the temocapril group, and 512 and
492 mmHg in the distilled water group, respectively. No
significant difference was detected in the respective basal re-
sponses between the groups. The beverage and temocapril
decreased the angiotensin I-induced pressor response to
457 mmHg at 60 min ( p0.05) and 282 mmHg at
10 min (p0.01), respectively, whereas the distilled water
hardly affected them (Fig. 1B). On the other hand, norepi-
nephrine-induced pressor response was not modified by the
administration of either the beverage, temocapril or distilled
water (Fig. 1C).
Effects on the Serum ACE Activity Figure 2 summa-
rizes the effects of the beverage and temocapril on the serum
ACE activity. The basal serum ACE activities were 39.41.2
IU/l in the beverage group (n6) and 36.91.4 IU/l in the
temocapril group (n6). No significant difference was de-
tected in the respective basal values between the groups. The
beverage slightly but significantly decreased the ACE activity
to 37.01.4 IU/l at 60 min (p0.01), whereas temocapril
suppressed it to 1.70.1 IU/l at 10 min (p0.01).
DISCUSSION
A new beverage made of red wine vinegar and grape juice
was recently demonstrated to activate the endothelial nitric
oxide synthase to exert vasodilation,
4)
resulting in the de-
crease of the blood pressure.
3)
In order to explore other po-
tential hypotensive mechanisms, in this study we analyzed
the effects of the beverage on the renin-angiotensin system in
vivo. As clearly shown in the functional as well as enzymatic
analysis, the p.o. administration of the beverage inhibited the
ACE activity of rats.
Of high interest in this study would be an identification of
potential mechanism related to the ACE inhibition by the
beverage. In previous studies, vinegar has been shown to
suppress the renin activity of spontaneously hypertensive
rats,
1)
to inhibit the ACE activity of the mouse pulmonary tis-
sue in vitro,
6)
and to reduce the blood pressure of the sponta-
neously hypertensive rats.
6,7)
On the other hand, ACE in-
hibitory effects have been identified in several polyphenols
derived from plant, such as tannin and procyanidins, which
are also present in grapes.
8,9)
Since currently analyzed bever-
age has been shown to contain certain amount of vinegar and
grape polyphenols,
3)
these previous knowledge may support
the idea that multiple components of the beverage may have
cooperatively suppressed the ACE activity in the in vivo rats.
The difference of the extent of serum ACE inhibition be-
July 2005 1209
Fig. 1. The Effect of the Red Wine Vinegar Beverage (Beverage), Dis-
tilled Water (d-Water) and Temocapril on the Angiotensin I-Induced
(1
m
g/kg, i.v.) and Norepinephrine-Induced (0.3—3
m
g/kg, i.v.) Pressor Re-
sponses in the Anesthetized Rat
A: Typical tracings of the effect of the beverage on the angiotensin I-induced pressor
responses. B: Summary of the effects of the beverage, distilled water and temocapril on
the angiotensin I-induced or norepinephrine-induced pressor responses. Data are ex-
pressed as the meanS.E. (n6 for each group). * p0.05, ** p0.01, compared to
the basal control values (C). BP: blood pressure, DMBP: increase in the mean blood
pressure.
Fig. 2. Summary of the Effects of the Red Wine Vinegar Beverage (Bev-
erage) and Temocapril on the Serum Angiotensin I-Converting Enzyme
(ACE) Activity
Data are presented as meanS.E. (n6). ** p0.01, compared to the basal control
values (C).
tween the beverage and temocapril also deserve a comment.
As shown in the results, the beverage decreased the an-
giotensin I-induced pressor response by 21%; however, the
extent of the inhibition of the serum ACE activity was only
7%. On the other hand, temocapril decreased the pressor re-
sponse by 48% and the extent of the inhibition of the serum
ACE activity was 95%. These results suggest that serum
ACE inhibition may not fully explain the change in the an-
giotensin I-induced pressor response in vivo. Indeed, some
drugs have been shown to decrease the blood pressure chiefly
through the ACE inhibition at target tissue like the blood ves-
sel and kidney.
10)
Similar profile has been reported for the
ACE inhibitory factors in the foodstuffs. For example, the
development of hypertension in spontaneously hypertensive
rats was inhibited by sour milk feeding, of which ACE activ-
ity in the aorta was significantly reduced, but that in the
serum was hardly affected.
2)
Therefore, one can speculate
that similar mechanism may have operated for the currently
analyzed beverage to suppress the angiotensin I-induced
pressor response.
In conclusion, the p.o. administration of the new beverage
suppresses the ACE activity in vivo, which may partly ex-
plain the previously demonstrated hypotensive action of the
beverage. More importantly, the beverage may be useful for
the prevention of the various cardiovascular diseases, includ-
ing the atherosclerosis, ventricular remodeling following my-
ocardial infarction, diabetic nephropathy, and hypertension,
of which ACE may play important roles for the onset.
Acknowledgements This study was supported in part by
Grant-in-aid from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan (#17590216), the Ya-
manashi Industry Support Organization, and the TV Ya-
manashi Science Development Fund.
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1210 Vol. 28, No. 7
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    A new non-alcoholic beverage made of red wine vinegar and grape juice (Budo-no-megumi) has been recently demonstrated to lower the blood pressure of human as well as rats. In this study, we pharmacologically analyzed the mechanism of its hypotensive action. The thoracic aorta with intact endothelium was isolated from Sprague-Dawley rats, and incubated with a Tyrode's solution. The beverage in concentrations of 0.25 to 2% relaxed the pre-contracted aorta with an alpha-adrenoceptor agonist phenylephrine in a concentration-dependent manner, 2% of which induced 59% relaxation. In contrast, the vasodilator response disappeared in the aorta without endothelium. L-Nitro-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, significantly reduced the vasodilator effect of the beverage, whereas indomethacin, an inhibitor of cyclooxygenase, hardly affected it. These results suggest that the beverage can activate the nitric oxide synthase activity to exert vasodilation, which may partly explain its previously reported hypotensive action.
  • Article
    It was determined that flavan-3-ols and procyanidins have an inhibitory effect on angiotensin I converting enzyme (ACE) activity, and the effect was dependent on the number of epicatechin units forming the procyanidin. The inhibition by flavan-3-ols and procyanidins was competitive with the two substrates assayed: N-hippuryl-L-histidyl-L-leucine (HHL) and N-[3-(2-furyl)acryloyl]-L-phenylalanylglycylglycine (FAPGG). Tetramer and hexamer fractions were the more potent inhibitors, showing Ki of 5.6 and 4.7 microM, respectively. As ACE is a membrane protein, the interaction of flavanols and procyanidins with the enzyme could be related to the number of hydroxyl groups on the procyanidins, which determine their capacity to be adsorbed on the membrane surface.