Research Article
Garlic
Powder Effect on Plasma Renin Activity, and Cardiovascular Effects of
Intravenous Angiotensin I and Angiotensin II in Normotensive and
Hypertensive Male Rats
Aliasghar Vahidinia 1, Behnam Heshmatian 2 * , Iraj Salehi 3, Mohammad Zarei 4 *
1 Department of Nutrition Sciences, School of Medicine, Hamadan University of Medical Sciences, Hamadan, IR Iran
2 Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, IR Iran
3
Chronic Diseases (Home Care) Research Center and Department of
Physiology, School of Paramedicine, Hamadan University of Medical
Sciences, Hamadan, IR Iran
4 Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, IR Iran
*Corresponding
authors: Mohammad Zarei, Department of Physiology, School of Medicine,
Hamadan University of Medical Sciences, Hamadan, IR Iran. Tel:
+98-8138380208, ; Behnam Heshmatian, Department of Physiology, School of
Medicine, Urmia University of Medical Sciences, Urmia, IR Iran. Tel:
+98-8138380464, Fax: +98-8138380208, E-mail: behhesh@yahoo.com Email: mmmzarei@yahoo.com
Abstract
Background: Hypertension
is amongst major health issues in developed countries, which results in
cardiovascular morbidity and mortality. Garlic plays an important role
in the reduction of hypertension.
Objectives: The
aim of the this study was to investigate the effect of consumption of
garlic powder on blood pressure and renin angiotensin system in a nitric
oxide deficiency hypertension model in male rats.
Materials and Methods: In
this study, thirty-two adult male Wistar rats (200 - 250 g) were
randomly divided to four groups as follows: normotensive,
normotensive-garlic, hypertensive and hypertensive-garlic. Oral
N-nitro-L-arginine methyl ester (L-NAME) was used to induce
hypertension. Normotensive-garlic and hypertensive-garlic groups were
fed 900 mg of garlic powder daily by oral gavage for forty-five days. At
the beginning of the experiments, systolic blood pressure was measured.
Immediately after the end of the experimental procedure animals were
anaesthetized by pentobarbital, blood samples were collected and, after
injection of angiotensin I, angiotensin II and captopril, blood pressure
was re-measured. Plasma renin activity was also measured.
Results: At
the beginning and at the end of experiments, systolic blood pressure was
higher in the hypertensive groups than the normotensive group. However,
at the end of the study, diastolic blood pressure and mean arterial
pressure were higher in the hypertensive groups than the normotensive
group. Angiotensin I level was low in the normotensive group whereas
plasma renin activity was high in the hypertensive group. After
different doses of injection of angiotensin I and angiotensin II, mean
arterial pressure was significantly increased in the normotensive-garlic
and the hypertensive-garlic groups, respectively. By using captopril,
mean arterial pressure and its changes were not significant after
injection of different doses of angiotensin I in different groups.
Conclusions: Garlic
powder consumption can reduce blood pressure, yet in this model, it did
not have an effect on the interaction between renin angiotensin system
and nitric oxide inhibition.
Keywords: Blood Pressure; Garlic; Renin-Angiotensin System; Rats
1. Background
It is believed that food
factors have a vital role on development of various human diseases such
as cardiovascular and metabolic diseases, atherosclerosis,
hyperlipidemia, thrombosis, diabetes and hypertension (1). Epidemiological studies have shown that diets rich in fruits, vegetables and spices decrease cardiovascular diseases (2-4). Garlic (Allium sativum) is known in many countries as a strong inhibitor of several diseases (5).
Garlic has selenium, oligosaccharides and flavonoids, which can promote
garlic efficacy. Garlic is full of flavonoids such as quercetin and
sulfur components, including allyl propyl disulfide, which is good for
human health. In addition, garlic and onion have sulfur contents such as
S-alkyl cysteine sulfoxide. These substances are turned to volatile
compounds, including thiosulfinates and polysulfides, by alliinase
enzyme during garlic crush (1, 6). Garlic, onion, green onion and scallion are the major sources Allium in the human diet. In Indian traditional medicine garlic is used for treatment of heart disease and arthritis (7).
Hypertension is an important disease, which is commonly diagnosed in developed countries (4).
Hypertension can induce degenerative diseases especially cardiovascular
disease. Many documents have indicated the effect of some functional
foods and nutrients (8, 9) on blood pressure, for example, garlic decreases blood pressure and aortic rigidity due to aging (6, 10, 11).
In a research done on a group of patients with high diastolic blood
pressure, garlic powder consumption for 12 weeks could decrease
diastolic pressure compared to the control group (10).
Another research on men with hypercholesterolemia, indicated that
garlic extract decreased systolic blood pressure compared to the control
group (12).
In a double blind study on healthy adults, consumption of garlic pill
three times per day for 12 weeks could not change blood pressure.
Changes in blood pressure were not observed in another study on patients
with hypercholesterolemia who consumed garlic (13). Mechanisms of the garlic effect on cardiovascular function are to increase nitric oxide synthase (NOS) activity (5), decrease prostaglandin production (14) and decrease Angiotensin (ANG) II (15). It has been reported that garlic decreases vessels wall thickness while ANG II increases vessels wall thickness (16, 17).
Angiotensin II is the main product of renin angiotensin system
(RAS), which affects adrenal cortex, brain, cardiovascular system and
kidneys (18). The RAS system is an important modulator of blood pressure and vascular function/disease (19, 20).
Furthermore, plasma renin activity and angiotensin converting enzyme
are important for determination of renin angiotensin system activity.
Plasma renin activity also affects the activity of constitutive NOS
(cNOS), which reduces secondary renin angiotensin system activity after
cNOS reinforcement (21).
Since nitric oxide (NO) has a central role in blood pressure
regulation, increasing NOS activity by garlic can interfere with the
anti-hypertensive effect of garlic. Chronic inhibition of NOS by
analogues of L-arginine, namely Nω-nitro-L-arginine-methyl-ester (L-NAME), can increase arterial blood pressure in rats.
2. Objectives
According to studies on
the effects of garlic on reducing blood pressure and stimulating NOS,
our research aimed to determine possible mechanisms of garlic on blood
pressure via renin angiotensin system after inhibition of NO production
by L-NAME. For this purpose, this experimental study included two groups
of rats with normal blood pressure and high blood pressure (with
L-NAME) to determine the effects of garlic powder on plasma renin
activity, angiotensinogen and cardiovascular system responses to
angiotensin I and II.
3. Materials and Methods
3.1. Animals
Thirty-two adult male Sprague-Dawley rats weighing between 200 -
250 g were purchased from the Pasteur institute of Iran. The animals
were kept in an animal room with 12 hours light/dark cycle with
temperatures ranging between 22 and 25°C. Rats were fed with standard
rat chow and given free access to tap water throughout the study. The
study was approved by the ethical committee of Hamadan University of
Medical Sciences. The animals were acclimatized for one week and were
randomly assigned to four groups: normotensive (C), normotensive-garlic
(CG), hypertensive (H) and hypertensive-garlic (HG).
3.2. Induction of Hypertension
For induction of hypertension, NO inhibitor or L-NAME (made by
the Fluca Company) was used. Drinking water containing L-NAME (370
μmol/L) within a black container (ad libitum) was given to the animals.
Water containing L-NAME was provided daily.
3.3. Feeding Method of Garlic
Nine hundred milligrams of garlic powder (Hamadan-Iran Grandis
Company) was dissolved in 2 mL of water and transferred to the animals’
stomach via a catheter, on a daily basis.
3.4. Blood Pressure Measurement
At the beginning and after induction of hypertension, the animals
were kept in a temperature-controlled restrainer. Indirect systolic
blood pressure was measured by using tail pressure cuff which was
connected to NARCO BIO system. At the end of study, the animals were
anaesthetized by pentobarbital (50 mg/kg; i.p.) and direct blood
pressure and its changes in response to injection of Ang I and Ang II
were measured via a catheter (PE-50) inserted into femoral artery. Blood
was taken for subsequent determination of plasma renin activity.
3.5. Different Injection Doses of Angiotensin I and II
Angiotensin I was dissolved in normal saline and concentrations of 10-4, 10-5, 10-6, 10-7, 10-8 and 10-9
M were prepared. These doses in a total volume of 0.1 mL were injected
via a catheter with one-minute intervals and the changing rate of
systolic and diastolic blood pressure was recorded. After blood pressure
stabilization in animals, different doses of angiotensin II with
concentrations of 10-4 to 10-9 M in the same
volume were injected to the femoral venues via a catheter with
one-minute intervals and the changing rate of systolic and diastolic
blood pressure were recorded in the animals again. At the end of this
section, captopril (10 mg/kg) in volume of 0.1 mL was injected and then
different doses of angiotensin I were re-injected using the
above-mentioned method and the changes of blood pressure were recorded.
3.6. Plasma Renin Activity Measurement
Plasma renin activity (PRA) was measured using the gamma coat PRA
radioimmunoassay kit (DiaSorin Inc). Plasma Renin activity was measured
at the end of the study.
3.7. Statistical Methods
The Statistical Package for Social Sciences (SPSS), version 16
was used for standard statistical analysis. Data were presented as mean ±
standard Deviation (SD). Student’s t-test and one-way Analysis of
variance (ANOVA) were used to determine the difference between groups,
and P < 0.05 denoted statistical significance.
4. Results
4.1. Blood Pressure
The results showed that systolic, diastolic and mean arterial
blood pressure weren’t significantly different in normotensive groups;
while in the normotensive-garlic group these variables had decreased (Figure 1).
In the hypertensive group, systolic, diastolic and mean arterial blood
pressure had increased compared to the beginning of the study although,
in the hypertensive-garlic group these variants had decreased.
|
Figure 1.
Systolic, Diastolic
and Mean Arterial Blood Pressure in Normotensive, Normotensive-Garlic,
Hypertensive and Hypertensive-Garlic Groups
|
4.2. Angiotensin I and Plasma Renin Activity
The lowest amount of serum angiotensin I was seen in the
normotensive group. In the normotensive-garlic group, serum angiotensin I
had significantly increased compared to the normotensive group. While
there was an increase in serum angiotensin I in the hypertensive group
compared to the normotensive group, it didn’t differ significantly in
the normotensive-garlic group (Table 1).
At the end of the study, the highest plasma renin activity was seen in
the hypertensive group while the lowest was in the normotensive group.
No significant difference was seen in plasma renin activity in the
normotensive-garlic group compared to the normotensive group. There was a
significant decrease in plasma renin activity in the
hypertensive-garlic group compared to the hypertensive group at the end
of the study (Table 1).
|
Table 1.
Serum Angiotensin I and Plasma Rennin Activity in the Normotensive and Hypertensive Groups
|
4.3. The Effect of Angiotensin and Captopril Injection on Vessels Responsiveness
The mean arterial blood pressure changes for different injection
doses of angiotensin I was significantly different in both normotensive
and normotensive-garlic groups. In the normotensive-garlic group, mean
arterial blood pressure changes in response to 10-6 - 10-9 M of angiotensin I injection was higher against 10-4 and 10-5
M doses in the normotensive group. Vessels responsiveness to different
doses of angiotensin I was not significantly different in the
hypertensive and hypertensive-garlic groups (Figure 2,
A). The mean arterial blood pressure showed significant changes for
different injection doses of angiotensin II in the normotensive group,
by decreasing at low doses and increasing at high doses. In the
normotensive-garlic group, mean arterial blood pressure significantly
increased at different doses. Thus, vessel responsiveness demonstrated
significant differences in the normotensive and normotensive-garlic
groups (Figure 2, B).
The mean arterial blood pressure at different injection doses
of angiotensin II showed an increase in the hypertensive group, while
this was not seen in the hypertensive-garlic group. As a result, the
responsiveness of vessels to injection of angiotensin II was
significantly different in the hypertensive-garlic compared to the
hypertensive group (Figure 2, B).
Mean arterial blood pressure in different animal groups
didn’t show statistically significant differences after captopril
injection. In the normotensive-garlic group after treatment with
captopril, the mean arterial blood pressure increased by higher doses of
angiotensin I injection although, angiotensin I concentrations was
equaled in other higher doses. These changes weren’t observed in the
normotensive group. The mean arterial blood pressure at different
injection doses of angiotensin I after treatment with captopril,
increased in the same manner for both hypertensive and
hypertensive-garlic groups (Figure 2, C).
|
Figure 2.
Mean Arterial Blood Pressure Change by Injection of 10-4 - 10-9
M/L of Angiotensin I (A), Angiotensin II (B), and Re-Injection of
Angiotensin I After Captopril (10 mg/kg)Intake (C), in Normotensive,
Normotensive-Garlic, Hypertensive and Hypertensive-Garlic Groups
|
5. Discussion
Results of this study
showed that inhibition of Nitric oxide (NO) production in treated groups
with L-NAME led to hypertension. However, in normotensive groups,
adding garlic powder to their diet could not decrease arterial blood
pressure significantly. Meanwhile, in hypertensive groups despite the
tendency to increase blood pressure, adding garlic to the subjects’ diet
did not make significant changes in arterial blood pressure.
Measurement of Plasma Renin Activity (PRA) showed that induction of
hypertension in hypertensive groups caused a significant increase in
PRA. Furthermore adding garlic to the subjects’ diet led to slight and
non-significant increase in PRA in groups, which had natural blood
pressure compared to the normotensive group, while in the hypertensive
group, garlic made a significant reduction in PRA compared to the the
non-treated group. Comparison of basal levels of angiotensin I showed
that adding garlic to the diet of the normotensive group led to an
increase in angiotensin I levels in this group, with this finding being
consistent with the slight rise of PRA in the normotensive group. On the
other hand, adding garlic to the diet of the hypertensive group caused a
slight and non-significant increase in angiotensin I compared to the
controlled hypertensive group. This finding is consistent with the
slight rise of PRA in the hypertensive group. One of the most striking
findings was the significant increase of angiotensin I level in
normotensive animals after adding garlic to their diet for a long
duration of time. This finding along with the increase of PRA in this
group indicated that the long-term consumption of garlic had stimulated
renin angiotensin system. Also this finding is consistent with the
results of other studies indicating that an increase of NO production
and reduction in arterial blood pressure and glomerular filtration in
kidneys may enhance active renin production through the kidneys (14, 22, 23).
After blood pressure reduction, glomerular filtration reduction is the
strongest and the main mechanism of physiological stimulation of active
renin production through the kidneys (24-26).
Besides, increasing of PRA is one the most important factors that
activates renin angiotensin system and leads to hypertension in the long
term (24-26).
Therefore, it is alarming for people with normal blood pressure and
long term and excessive consumption of garlic and again it reminds about
the principle of balance in the diet. It was observed that adding
garlic to the diet of hypertensive animals led to a slight increase in
arterial blood pressure. Hypertension models that have been induced by
inhibition of NO production, in this study and previous studies,
indicated garlic’s intervention in NO production process. Our findings
demonstrated that in hypertensive animals according to inhibition of NO
production by L-arginine analog, not only reduction did not occur, but
also a slight increase occurred in the average level of arterial blood
pressure. This increase indicates changes in vascular endothelium,
because vascular endothelium is the main place for both NO production
and Angiotensin converting enzyme (ACE) production and is also the place
for vascular effects of Angiotensin II (27, 28).
Previous studies have shown that the levels of NO production in
vascular endothelium affect the activity of ACE and receptors of
angiotensin II (29-31).
The results of intravenous infusion of angiotensin I on blood
pressure in the studied groups showed that induction of hypertension
significantly increased response to dilute doses of angiotensin I.
Angiotensin I does not have direct biological effects and it should be
converted to angiotensin II by ACE to act its roles (32).
Therefore, probable causes of these changes can be increasing of ACE
activity and/or increasing of angiotensin II receptors. Whereas changes
that are created by response to angiotensin I are more tangible than
those changes created by response to angiotensin II (affected by
induction of hypertension), the possibility of changes in ACE activity
is more likely, because because opposite to the angiotensin I, response
to angiotensin II is independent of ACE. Moreover, inhibition of NO can
cause an increase in the number of angiotensin II receptors and also
produce ACE in endothelium (30, 31),
therefore this part of our findings is consistent with the results of
other studies. On the other hand, the investigation of the response to
angiotensin I, after inhibition of ACE by treatment with captopril,
indicates that captopril vehemently reduces response to angiotensin I,
and also arterial blood pressure in animals of control normotensive
group. Also this finding can be the reason for the increase in
conversion of angiotensin I to angiotensin II as the most likely change
through induction of hypertension. It should be mentioned that in
addition to ACE, other enzymes such as kimase and tonin are also able to
convert angiotensin I to angiotensin II (33, 34). It is interesting to know that other studies have indicated the intervention of NO in producing kimase (35).
Moreover, the results of this study showed that adding garlic to the
diet of both normotensive and hypertensive animals increases response to
angiotensin I rather than angiotensin II. In simpler terms, adding
garlic to the diet has shifted the dose-response diagram of angiotensin I
and angiotensin II to the left and has increased sensitivity to these
two peptides. Alignment of these changes in response to angiotensin I
and angiotensin II indicates that the process of response to angiotensin
II at the receptor’s level and or mediation in response at the receptor
or post-receptor levels may be affected by garlic powder. Also
angiotensin II in addition to vessels can change blood pressure and
heartbeat by affecting the central nervous system (24, 36).
This part of the findings is confirmed by garlic’s effects on arterial
blood pressure in normotensive and hypertensive animals. We used garlic
powder in this study, because this product is crude and not divided,
thus there may be some materials in garlic garlic which affect
endothelial or RAS function. The results of this study are inconsistent
with the results of Sharifi et al., which have shown that fresh garlic
can inhibit Goldblatt hypertension (37).
Meanwhile, our other study showed that garlic powder does not affect
hypertension induction in two-kidney-one-clip (2K1C) rats (38).
The comparison of our previous study with Sharifi’s study, suggests
that fresh garlic and garlic powder may affect the hypertension process
and function of renin angiotensin system differently.
Acknowledgments
The authors gratefully acknowledge the research
center for molecular medicine of Hamadan University of Medical Sciences,
Hamadan, Iran, for their financial support.
Footnotes
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