Impact of Tannic Acid On Blood Pressure, Oxidative Stress and Urinary Parameters in L-NNA-induced Hypertensive Rats
Impact of Tannic Acid On Blood Pressure, Oxidative Stress and Urinary Parameters in L-NNA-induced Hypertensive Rats
Impact of Tannic Acid On Blood Pressure, Oxidative Stress and Urinary Parameters in L-NNA-induced Hypertensive Rats
DOI 10.1007/s10616-013-9661-4
ORIGINAL RESEARCH
Received: 23 July 2013 / Accepted: 18 October 2013 / Published online: 5 December 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract Hypertension is a major health problem were determined in blood plasma and homogenates of
with increasing prevalence around the world. Tannic heart, liver and kidney. In order to evaluate renal
acid is water-soluble polyphenol that is present in tea, functions, urine pH, urine volume, urine creatine, uric
green tea, coffee, red wine, nuts, fruits and many plant acid, and urea nitrogen values were measured. Com-
foods. It has been reported to serve as an antioxidant or pared with the hypertension group, a decrease in MDA
a pro-oxidant depending on the type of cells and its concentrations of heart tissue (p \ 0.01), urea nitro-
concentration. The purpose of our study was to gen values (p \ 0.01) and urine volumes (p \ 0.001)
evaluate the effect of tannic acid on systolic blood were established in hypertension ? tannic acid group.
pressure, oxidative stress and some urinary parameters There was also a decrease in blood pressure values
in the rat model of essential hypertension. Blood (20th and 30th days) of this group, but there was no a
pressures of all rats were measured using the tail-cuff statistical difference according to hypertension group.
method. The nitric oxide synthase inhibitor N The findings of our research show the effect of tannic
(omega)-nitro-L-arginine was administered orally at acid in lowering blood pressure in hypertensive rats.
a dose of 0.5 g/l/day for 15 days to rats in order to
create an animal model of hypertension. Tannic acid Keywords Hypertension Tannic acid
was intraperitoneally injected at a dose of 50 mg/kg Systolic blood pressure Oxidative stress
for 15 days. Superoxide dismutase, catalase activity Urinary parameters
and the concentration of malondialdehyde (MDA)
Introduction
D. Turgut Coşan (&) F. Saydam C. Özbayer
A. Soyocak H. V. Güneş İ. Değirmenci
H. Kurt M. C. Üstüner
Hypertension (HT) is a significant health issue with a
Department of Medical Biology, Faculty of Medicine, gradually increasing prevalence. It was reported to
Eskişehir Osmangazi University, Eskisehir, Turkey have affected 972 million people around the world and
e-mail: [email protected] to have a prevalence of 26.4 % in the year 2000. It is
F. Doğaner
foreseen to have a prevalence of 29.2 % by 2025 and
Department of Biology, Faculty of Arts and Sciences, to affect 1 billion 56 million people (Kearney et al.
Aksaray University, Aksaray, Turkey 2005). HT is an important risk factor for stroke,
myocardial infarction, cardiac and renal failure. HT is
C. Bal
Department of Biostatistics, Faculty of Medicine,
predicted to cause 7.1 million early deaths around the
Eskişehir Osmangazi University, Eskisehir, Turkey world. According to data of the World Health
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Organization collected in 2000, HT ranks first among hydrolyzed tannins, tannic acid, is found in green
the preventable deaths in the world (World Health tea, coffee, red wine, such nuts as hazelnuts and
Organization 2003). walnuts, fruits, and most plants (Cowan 1999; Taffe-
Reactive oxygen species (ROS) that contain an tani et al. 2005; Marienfeld et al. 2003; Cosan et al.
unpaired electron in the final orbit of their atomic 2009). Tannic acid has major biological activities such
structures, highly reactive, and are endogenously as anticarcinogenic, antioxidant, antimutagenic, anti-
synthesized side products. If not immediately detox- microbial, antiallergic, antiinflammatory, and stop-
ified where they are synthesized, ROS can cause ping bleeding (Labieniec and Gabryelak 2006; Cowan
numerous diseases including hypertension. ROS were 1999; Marienfeld et al. 2003). In addition, tannic acid
shown to stimulate the growth and proliferation of can serve as antioxidant or prooxidant depending on
vein smooth muscle cells (Ruiz-Gutierrez et al. 2001; the cell type used and its concentration (Labieniec and
Kour and Perkins 1991). Gabryelak 2003). Polyphenols are also known to have
Substances that prevent or postpone the oxidation an antihypertensive effect (Rodrigo et al. 2012).
of substances that can be oxidized such as protein, Along with the discovery of nitric oxide (NO) in
lipid, carbohydrates, and DNA found in live cells are 1980s, researches were focused on the correlation of
called antioxidants, and such reactions carried out by blood pressure increase with the reduction in NO
antioxidants are defined as antioxidant defense. This synthesis. NO is synthesized by nitric oxide synthase
system demonstrates itself by preventing excessive (NOS) enzymes from L-arginine. A hypertension
production of free radicals or by reducing or repairing model was developed that is based on the increase in
the damage. These systems contain such endogenous arterial blood pressure as a result of chronic inhibition
enzymes as superoxide dismutase (SOD), catalase of NOS enzymes with such L-arginine analogues as
(CAT) and glutathione peroxidase (GPx) (Ozbayer NG-nitro-L-Arginine (L-NNA), and NG-nitro-L-argi-
et al. 2011). nine methyl ester (L-NAME) (Ribeiro et al. 1992).
Oxidative stress level increases in hypertension and Chronic NOS inhibition is commonly used in essential
in relation to that, reactive oxygen species release hypertension research. Chronic NOS inhibition of total
shows a rise. Increase in malondialdehyde (MDA) that peripheral resistance increase, increased renal sodium
is the final product of lipid peroxidation which causes involvement, sympathetic system activation, and var-
oxidative stress is another physiological characteristic ious vasoactive substances is accepted to provide
of hypertension. High ROS amount inhibits the mediated hypertension (Zatz and Baylis 1998).
activity of antioxidants such as SOD and CAT and The aim of this study is to investigate the effects of
decreases the antioxidant capacity. In a study that tannic acid on antioxidant system and renal functions
compared the blood samples of essential hypertensive disrupted by hypertension, increased free radicals, and
patients and normotensive individuals, high level of blood pressure. Thus, the effects of tannic acid in
MDA concentration was established, and in addition, essential hypertension model on systolic blood
the presence of low SOD activity was also shown pressure and values of SOD, MDA, and CAT in
(Russo et al. 1998). This demonstrates that oxidative blood, heart, liver, and renal tissues were investigated.
stress plays an important role in the pathogenesis of In order to evaluate the effect of tannic acid on renal
essential hypertension. functions, urine pH, urine volume, urine creatine, uric
Fruits and vegetables rich in polyphenol, and drinks acid, and urea nitrogen values were measured.
such as tea and wine, act as inhibitors and are
protective for various human cancers and cardiovas-
cular diseases (Gulcin et al. 2010). Tannins found in Materials and method
such food are divided into two classes as hydrolyzed
and condensed tannins (Labieniec and Gabryelak Twenty eight female Spraque–Dawley rats of
2006; Cowan 1999; Cosan et al. 2011). Polyphenols 250–300 g weight and aged 4–5 months were used
containing tannin possess biological activities as in the experiment. Rats were placed in special cages in
antitumor, antiviral, anti-HIV, lipid peroxidation groups of seven and were applied care under standard
inhibition, and plasmin activity (Labieniec and Ga- conditions (12 h of daylight, 12 h of dark, ventilated,
bryelak 2003; Cosan et al. 2010). Among the fixed temperature rooms). Standard rat pellet food of
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8 mm was given to rats for nourishment and tap water each rat was obtained from left ventricle of the heart and
was provided as drinking water. Weight increases of put in EDTA tubes. Heart, liver, and kidney tissues were
the subjects were measured with an electronic scale taken and frozen in liquid nitrogen. Following hemo-
(Chyo MP-300 electronic balance, Chyo Balance globin measurement, hemolysates were prepared from
Corp, Kyoto, Japan) at the beginning and in the end blood samples taken to EDTA tubes and homogenates
of experiment. Approval was obtained for our study were prepared from frozen heart, liver and kidney
from the Experimental Animals Local Ethics Com- tissues, and protocols necessary for SOD, MDA, and
mittee of Eskisehir Osmangazi University (Ethics CAT measurements are carried out. Erythrocyte hem-
Committee Ref No: 188/2011). olysates were prepared by using the method reported by
Rats were divided into four experimental groups Sun et al. (1988). Blood samples were taken to 2 ml
with seven rats in each group. Substances adminis- EDTA tubes and plasma and erythrocyte were separated
tered to experimental groups, duration, and amounts in centrifuge. Erythrocyte pellet left in the tube was
are given in Table 1. washed with 0.9 % NaCl (normal saline) three times
Daily L-NNA and tannic acid amounts to be and hemolysate was formed. The protocol used by Kiris
administered to rats were estimated according to et al. (2008) was applied for the preparation of tissue
planned concentrations (Ribeiro et al. 1992; Krajka- homogenates. The prepared hemolysates and homoge-
Kuzniak et al. 2008). A study by Ribeiro et al. (1992) nates were stored at -80 °C until the measurements of
that defined first the experimental hypertension model SOD, MDA, and CAT. SOD activity was spectropho-
with chronic nitric oxide synthase inhibition was taken tometrically measured with the SOD Determination Kit
as reference and L-NNA was administered to rats. (Fluka, St. Louis MO, USA, Cat. No: 19160) that is
Systolic blood pressure measurements were carried out based on WST (water-soluble tetrazolium salt) reaction.
from the tail by the indirect ‘‘tail-cuff’’ method (MAY Enzyme activity of the samples was established with
BPHR 9610-PC tail-cuff indirect blood pressure ELISA at 450 nm by the inhibition of formazan dye
recorder, Commat Ltd., Ankara, Turkey) without the based on xantin–xantin oxidase enzymatic method
use of anesthetics on the day before the administration that produces superoxide radicals. The results
of L-NNA and on the 15th, 20th, and 30th days were put in their respective places in SOD inhibi
following the beginning of the experiment. After blood tion % = {[(Ablank1 - Ablank3) - (Asample - Ablank2)]
pressure measurements were conducted on the 30th day, /(Ablank1 - Ablank3)} formula and was expressed as %
rats were taken to urine collection cages labeled based inhibition (Ablank1, Ablank2, and Ablank3 are the absor-
on groups and their 18-h urine samples were obtained. bance values of standard solutions that are prepared with
Following the determination of volumes of collected the kit; Asample is the absorbance value of the sample
urine samples, pH values of each sample were measured solution). CAT activity was established by spectropho-
with a pH meter (inoLab pH 720, WTW Laboratory, tometric evaluation of hydrogen peroxide that formed a
Weilheim, Germany). Other urine parameters were stable complex with ammonium molybdate (Goth
analyzed spectrophotometrically. After the urine col- 1991). Absorbance values of B1 (Blank 1), B2 (Blank
lection process, rats were put to sleep with ether 2), B3 (Blank 3) and sample tubes against 405 nm
anesthesia and approximately 2 ml blood sample of distilled water were measured in spectrophotometer.
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Then, catalase activity of each samples was determined IBM SSPSS for Windows 20.0 software pack. Shap-
with the formula CAT activity (kU/L) = [(Abssample - iro–Wilk test was used for establishing the distribution
Absblank1)/Absblank2 - Absblank3)] 9 271 (Absblank1, forms of the data. Blood pressure data were assessed
Absblank2, and Absblank3 are absorbance values of with Student’s t-test and in vitro data were evaluated
standard solutions that are prepared according to Goth with one-way ANOVA. In multiple comparisons,
(1991)). MDA concentration was established accord- Bonferroni test that is among the post hoc tests was
ing to the method based on color reaction of MDA with used. p \ 0.05 values were accepted to be statistically
thiobarbituric acid (TBA) (Mihara and Uchiyama significant.
1978). Absorbances of blind and sample tubes were
read following zeroing with distilled water at 532 nm
in spectrophotometer. Defined with nmol/ml, MDA Results
concentration was expressed in nmol/gHb according to
hemoglobin (g/dl) value given in ‘‘optic densities and In the 15th day measurements of 3rd and 4th groups,
hemoglobin g/dl’’ table by Tanyer for erythrocyte blood pressure values were observed to have increased
hemolysates (Tanyer 1985). compared to the control group and the 2nd group.
For urea nitrogen measurement, transformation of There was a statistically significant difference in this
urea to ammonium carbonate by degrading it with urease increase (p \ 0.001). A difference was not observed
enzyme and its colorimetric measurement of a yellow between the control group and the 2nd group in terms
color formed by Nessler’s reagent was taken as the basis of blood pressure values (p [ 0.05). It was observed
(Urease-Nesslerization method). Uric acid amount was that the 20th day measurement value of the 4th group
established by the colorimetric measurement of the blue decreased compared to the 15th day and approached to
color formed by uric acid reducing phosphotungstic acid the control group values. A decrease was established
in mild acidic and sodium carbonate environment in blood pressure values (20th and 30th days) of rats
(modified Caraway method). The amounts of creatinine (4th group) that were administered intraperitoneal
in urine samples were measured by the alkaline picrate tannic acid 15 days after hypertension was created
method (Jaffe’s alkaline picrate reaction assay) which is compared to the hypertension group. These values
based on the colorimetric measurement using a spectro- were approaching the control group but a statistical
photometer of the orange color formed as a result of difference was not observed (Table 2).
creatinine transforming picric acid into picramic acid in When compared the hemolysate, heart, and kidney
an alkali environment. samples between the groups in terms of SOD enzyme
activation, no statistical difference was established.
Statistical analysis However, SOD activation of liver homogenate sam-
ples of rats in the 4th group demonstrated a statistically
The data were summed up as means ? SD. Statistical significant drop compared to the 2nd group (p \ 0.05)
evaluation of the obtained data was carried out with (Table 3).
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Table 3 SOD inhibition values of hemolysate, heart, liver and kidney samples in the experimental groups and their statistical
analysis
Groups SOD inhibition %
Hemolysate Heart Liver Kidney
Table 4 CAT enzyme values of hemolysate, heart, liver and kidney samples in the experimental groups and their statistical analysis
Groups Catalase
Hemolysate (kU/mg Hb) Heart (kU/ml) Liver (kU/ml) Kidney (kU/ml)
When comparing the CAT enzyme values in the Urine volume was established to increase in the 3rd
hemolysate samples of the experimental groups, a (p \ 0.001) and 4th group (p \ 0.001) compared to
decrease was established in the 4th group (p \ 0.01) the controls. It was also established that urea nitrogen
compared to the control group. When analyzing the values increased in the 3rd group compared to the
CAT enzyme values in the homogenate samples of the control group (p \ 0.001) and that these values in the
cardiac tissue, a decrease was observed in the 2nd 4th group drew near to the control group. It was
group (p \ 0.01) compared to the control group. observed that the uric acid values increased in the 3rd
While a change was not observed in the CAT enzyme group (p \ 0.001) and in the 4th group (p \ 0.001)
activity of liver tissues, kidney CAT values were compared to the control group, and that such an
established to decrease in the 4th group compared to increase in the 4th group was lower. Urine creatine
the 2nd group (p \ 0.05) (Table 4). values were observed to rise in the 3rd group
When comparing the MDA concentrations of the compared to the control group (p \ 0.001). Although
hemolysate samples, an increase in the concentration an increase was found in the 4th group (p \ 0.001), it
was determined in the 4th group compared to the 2nd was established to be lower than the 3rd group
group (p \ 0.05). When analyzing the homogenate (Table 6).
samples of heart tissue, a decrease in the MDA amount
was established in the 4th group compared to the
control group (p \ 0.001). When comparing the MDA Discussion
concentrations of the homogenate samples of liver
tissue, an increase was observed in the 2nd group It was demonstrated in various studies that reactive
compared to the control group (p \ 0.05). MDA oxygen species (ROS) that are endogenously synthe-
amount was observed to increase in homogenate sized in the human body and that can easily undertake
samples of kidney tissue in the 4th group compared to electron exchange with other molecules play an impor-
the 2nd group (p \ 0.05) (Table 5). tant role in the pathogenesis of hypertension (Ruiz-
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Table 5 MDA concentrations of hemolysate, heart, liver and kidney samples in the experimental groups and their statistical analysis
Groups MDA concentrations
Hemolysate (nmol/gHb) Heart (nmol/ml) Liver (nmol/ml) Kidney (nmol/ml)
Table 6 The values of urinary parameters of the experimental groups and their statistical analysis
Groups Volume (ml) pH Urea nitrogen Uric acid Urine creatine
(mg/dl) (mg/dl) (mg/dl)
1. Control 4.98 ± 0.21a,b,c 7.91 ± 0.29b 1,568.93 ± 18.44b 8.48 ± 0.30e,b,c 43.56 ± 1.30b,c
2. Tannic acid 4.52 ± 0.30d,b,c 7.67 ± 0.16c,f 1,563.43 ± 12.02b 8.07 ± 0.24j,b,c 42.82 ± 0.65b,c
,a,c ,e,c ,a,i ,a
3. Hypertension 6.77 ± 0.23* 7.28 ± 0.19* 1,614.81 ± 16.81* 9.42 ± 0.39* 57.99 ± 6.27*,a
,a,b g,b h ,a
4. Hypertension ? tannic acid 5.89 ± 0.24* 8.13 ± 0.26 1,582.23 ± 8.80 9.13 ± 0.09* 54.13 ± 3.72*,a
Compared with the control group * p \ 0.001, d p \ 0.01, j p \ 0.05. Compared with the tannic acid group a p \ 0.001, e p \ 0.05, g
p \ 0.01. Compared with the hypertension group b p \ 0.001, f p \ 0.05, h p \ 0.01. Compared with the hypertension ? tannic acid
group c p \ 0.001, i p \ 0.01. The data were summed up as means ? SD
Gutierrez et al. 2001). Consuming food that has free to the hypertension group showing the blood pressure
radical scavenging antioxidant characteristics is an reducing effect of tannic acid in hypertensive rats.
important strategy to prevent hypertension. Therefore, The effect of tannic acid on hypertension was
we aimed to investigate the effect of tannic acid which is indirectly investigated by using nutrients containing
an hydrolyzed tannin shown to have free radical tannic acid. Porteri et al. (2010) found that red wine
scavenging properties on essential hypertension. showed a dose-dependent vasodilator effect on
Systolic blood pressure measurements on the 15th patients with essential hypertension and they sug-
day in 3rd and 4th group administered L-NNA to gested that such an effect was created by polyphenols
create hypertension was established to increase. Oktar or tannic acid contained in red wine. The effect of
et al. (2008) administered 0.45 g/l L-NNA in drinking proanthocyanidin that is among condensed tannins on
water to rats for 10 days and found a rise in blood vein endothelium was investigated in hypertensive
pressure values similar to our study. Likewise, the rise rats, and its antihypertensive and vasodilator effect
seen in our study demonstrates that essential hyper- was established (Kawakami et al. 2011). Similar to
tension model occurred in the 3rd and 4th group. The these studies, the effects of nutrients containing
fact that a significant difference was not found in blood polyphenols or tannin on hypertension were analyzed
pressure values between the control group and the 2nd but the effect of tannic acid that is among the directly
group shows that tannic acid does not have an effect on hydrolyzed tannins as an active ingredient was not
blood pressure values in normotensive rats. A decrease investigated. In order to develop new understandings
was observed in 20th and 30th day blood pressure and treatment methods, it is important to put forth
values of the hypertension group which was statistical whether natural compounds such as tannic acid have a
different with respect to other initial measurements. specific effect.
This difference may stem from the dose-dependent Kidneys play an important role in keeping the blood
effect of L-NNA administration. Blood pressure pressure within a healthy interval, and thus, blood
values were found to be low in the 4th group compared pressure exceeding a normal level initially affects
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Cytotechnology (2015) 67:97–105 103
kidneys. It was suggested that removing waste mate- antioxidant levels in L-NAME-induced hypertensive
rials and excess fluid from the body would be difficult rats (Saravanakumar and Raja 2011). Increase in blood
due to damaging blood vessels and filtration in pressure in hypertension stems from complex interac-
kidneys, and thus, the excess fluid remaining in the tions in such numerous systems as heart, kidney, brain,
blood vessels would raise blood pressure (Zatz and liver, and veins (Touyz and Briones 2011). Thus, we
Baylis 1998). Therefore, in our study, by measuring investigated the balance condition of free radical–
certain urine parameters we aimed to find out how antioxidant in such organs as heart, kidney, and liver in
hypertension and tannic acid would affect renal hypertension and whether tannic acid has an effect on
functions in dependence of the doses we used. Baylis it.
et al. (1992) found that chronic nitric oxide synthase We established antioxidant status by analyzing
inhibition method that we also used in our study SOD and CAT levels in various organs, and free
created renal damage. Similar to that study, we also radical release level by determining MDA concentra-
established a statistical increase in urea nitrogen, uric tion. It was observed that tannic acid did not cause a
acid and urine creatinine values depending on renal change in the SOD enzyme level in heart and blood
dysfunction in the hypertension group. In their study following hypertension. The fact that tannic acid
that investigated the toxicity of tannic acid, Robinson administered following hypertension reduced SOD
et al. established that tannic acid suppress urine levels in liver leads to believe that tannic acid does not
production when injected intraperitoneally to rats have a positive effect on liver in hypertension.
(Robinson and Graessle 1943). In agreement with However, an increase was observed in the inhibition
Robinson and Graessle, we found that urine volume values of SOD enzyme of hemolysate and kidney, but
decreased in tannic acid group compared to the control this was not statistically significant. When analyzing
group. In addition, we also observed that tannic acid catalase enzyme levels, it was observed that tannic
we administered after hypertension was created acid had a reducing effect on antioxidants in hemol-
caused a decrease in urine volume compared to ysate and kidney samples. There was not an effect of
hypertension group. When checked through urine tannic acid on heart and liver samples. In the
volume, it may be suggested that tannic acid has a hypertension model, it was established that only
reducing effect of hypertension. We did not come tannic acid had a reducing effect on MDA concentra-
across with a literature reference demonstrating the tion in heart samples. In a recent study carried out
effect of tannic acid on urea nitrogen and uric acid in vitro, it was demonstrated that tannic acid had a free
values. To sum up, we statistically established that radical sweeping effect and that it increased antiox-
tannic acid has an improving effect on renal functions idant levels while reducing lipid peroxidation (Gulcin
in the hypertension model. et al. 2010). On the other hand, tannic acid was
Oxidative stress is a multisystem case that includes reported to have a pro-oxidant capacity by creating
heart, kidney, nervous system, veins, and immune hydroxyl radical in the presence of copper (Khan et al.
system in hypertension. If reactive oxygen species or 2000). A study reported that there were low SOD
free radicals that occur as a result of oxidative stress activity, high MDA concentration and low level of
are not inhibited, they may easily enter electron CAT activity in blood samples of hypertensive
exchange thanks to the potential they possess. Thus, individuals compared to normotensive individuals.
the balance between free radicals and antioxidant We also observed that CAT activity levels were low in
disrupts, and a pathologic environment is occured the blood samples.
(Touyz and Briones 2011). In order to reduce the Based on these findings, tannic acid was observed
increasing oxidative stress potential in hypertension, it to have a reducing effect on blood pressure in
was observed in recent years that the protective hypertensive rats. Absence of a statistical difference
characteristics and effect mechanisms of exogenous may be the result of dose or other physiological
antioxidants has been in focus. Phenolic compounds interactions. It was observed that tannic acid has a
attract the attention of researchers the most. It was reducing effect on urine volume, urea nitrogen, uric
shown that veratric acid which is a phenolic compound acid, and urine creatinine levels determined to
just like tannic acid reduced blood pressure and lipid increase in hypertensive rats, however, that the said
peroxidation, increased enzymatic and non-enzymatic effect on uric acid and urine creatinine was not found
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to be statistically significant. In addition, it was Khan NS, Ahmad A, Hadi SM (2000) Anti-oxidant, pro-oxidant
observed that tannic acid may cause a statistically properties of tannic acid and its binding to DNA. Chem
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significant increase in hemolysate and SOD levels in Kiris I, Kapan S, Kilbas A, Yilmaz N, Altuntas I, Karahan N,
kidney in hypertension model, and it may also cause a Okutan H (2008) The protective effect of erythropoietin on
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