Download Magnesium nitrate attenuates blood pressure rise in SHR rats

Magnesium Research 2014; 27 (1): 16-24
ORIGINAL ARTICLE
Magnesium nitrate attenuates blood
pressure rise in SHR rats
Reinis Vilskersts1,2, Janis Kuka1, Edgars Liepinsh1, Helena Cirule1, Anita Gulbe1,
Ivars Kalvinsh1 , Maija Dambrova1,2
1 Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia; 2 Rigas
Stradins University, Dzirciema Str. 16, Riga, LV-1007, Latvia
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Correspondence: R Vilskersts. Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV-1006, Latvia
<[email protected]>
Abstract. The administration of magnesium supplements and nitrates/nitrites
decreases arterial blood pressure and attenuates the development of
hypertension-induced complications. This study was performed to examine the
effects of treatment with magnesium nitrate on the development of hypertension and its complications in spontaneously hypertensive (SHR) rats. Male SHR
rats with persistent hypertension at the age of 12-13 weeks were allocated to two
groups according to their arterial blood pressure. Rats from the control group
received purified water, while the experimental animals from the second group
received magnesium nitrate dissolved in purified water at a dose of 50 mg/kg.
After four weeks of treatment, blood pressure was measured, the anatomical
and functional parameters of the heart were recorded using an ultrasonograph,
vascular reactivity was assayed in organ bath experiments and the cardioprotective effects of magnesium nitrate administration was assayed in an ex vivo
experimental heart infarction model. Treatment with magnesium nitrate significantly increased the nitrate concentration in the plasma (from 62 ± 8 ␮mol/l
to 111 ± 8 ␮mol/L), and attenuated the increase in the arterial blood pressure. In the control and magnesium nitrate groups, the blood pressure rose by
21 ± 3 mmHg and 6 ± 4 mmHg, respectively. The administration of magnesium
nitrate had no effect on the altered vasoreactivity, heart function or the size
of the heart infarction. In conclusion, our results demonstrate that magnesium
nitrate effectively attenuates the rise in arterial blood pressure. However, a longer period of administration or earlier onset of treatment might be needed to
delay the development of complications due to hypertension.
Key words: magnesium nitrate, hypertension, spontaneously hypertensive rat,
heart infarction, vascular reactivity
tion with relatively inexpensive macro-elements
[3] and inorganic ions such as nitrate and nitrite
[4, 5].
Nitrite and nitrate are naturally occurring
anions found in vegetables and meats. For a long
time, it was thought that the ingestion of both
of these nitrogen-containing anions increased the
incidence of oncological diseases. However, recent
data from toxicological studies do not support
this statement [6]. Instead, it has been concluded that dietary nitrates and nitrites may play
a significant role in cardiovascular health [4, 5].
16
To cite this article: Vilskersts R, Kuka J, Liepinsh E, Cirule H, Gulbe A, Kalvinsh I, Dambrova M. Magnesium nitrate attenuates
blood pressure rise in SHR rats. Magnes Res 2014; 27(1): 16-24 doi:10.1684/mrh.2014.0358
doi:10.1684/mrh.2014.0358
Essential hypertension is a disease that affects
more than 1.5 billion people worldwide [1].
Elevated blood pressure is considered to be a
main risk factor for the development of various
diseases involving more than just the cardiovascular system [2]. Thus, the discovery of new
antihypertensive drugs remains a challenging
field of research. Although new drug candidates
and novel surgical approaches to treat hypertension are still being developed, it has been
shown that elevated blood pressure can be lowered
with lifestyle changes and dietary supplementa-
Copyright © 2017 John Libbey Eurotext. Téléchargé par un robot venant de 88.99.165.207 le 04/05/2017.
Magnesium nitrate attenuates blood pressure rise
In previous studies, treatment with nitrates or
nitrites has lowered blood pressure in experimental animals [7, 8] as well as in humans
[9]. Bryan and colleagues demonstrated that
the administration of nitrite and nitrate protected the heart against ischemia/reperfusion
injury [10]. Moreover, treatment with nitrate and
nitrite has demonstrated vasoprotective effects
[9, 11, 12]. The pharmacological effects of nitrates
and nitrites have mainly been attributed to their
ability to be converted in vivo to nitric oxide (NO)
[4, 5].
Magnesium supplementation has shown similar cardiovascular effects as nitrate and nitrite
administration [13]. As with nitrate administration, magnesium supplementation has been
shown to reduce blood pressure in retrospective
clinical studies [3] as well as in an experimental
animal model [14]. The administration of additional magnesium in an experimental model of
atherosclerosis in cholesterol-fed rabbits attenuated the development of atherosclerotic lesions [15].
Moreover, the vasoprotective effects of magnesium
supplementation were observed in an experimental model of autosomal recessive, ectopic
mineralising disorder [13], and in a case of balloon
injury-induced endothelial dysfunction [16]. The
pharmacological effects of magnesium ions have
been attributed to their ability to act as an antagonist of calcium channels. In addition, magnesium
ions stimulate the production of NO and vasodilator prostacyclins, and alter the vascular responses
to vasoconstrictive agents [17].
In this study, we evaluated the effects of concomitant treatment with both magnesium ions and
nitrate in the form of magnesium nitrate on the
development of hypertension and its complications. In previous studies, it has been shown that
in cases of the simultaneous administration of two
or more different blood pressure lowering drugs,
the hypotensive effect is potentiated [18, 19].
Thus, we hypothesised that treatment with both
ions might have synergistic, hypotensive effects.
The effect of the administration of magnesium
nitrate was studied in an experimental model of
hypertension, spontaneously hypertensive (SHR)
rats, which is a widely used experimental model
for the study of blood pressure lowering agents
[20]. The dose of magnesium nitrate was chosen to
be equimolar to the dose of nitrates used in a previous study [10] with the corresponding amount of
magnesium.
Materials and methods
Chemicals
Sodium pentobarbital (Narkodorm) solution
was purchased from Alfasan (Woerden, The
Netherlands). Heparin sodium was purchased
from Panpharma (Fougeres, France). Magnesium
nitrate hexahydrate, sodium chloride, potassium
chloride, calcium chloride dihydrate, magnesium
chloride hexahydrate, sodium hydrogencarbonate, potassium dihydrogenphosphate, glucose,
ethylenediaminetetra-acetic
acid
(EDTA),
L-phenylephrine hydrochloride, sodium nitroprusside (SNP) and acetylcholine chloride were
purchased from Sigma (Schnelldorf, Germany).
Experimental animals
Male, 8- to 9-week-old SHR rats (n=18), weighing
140 to 150 g were obtained from the Harlan
Laboratories (Great Britain) and housed under
standard conditions (21-23◦ C, 12-hour light/dark
cycle, relative humidity 45%-65%), with unlimited
access to food (R70 diet, Lactamin AB, Kimstad,
Sweden) and water. The R70 diet contained 0.25%
w/w magnesium. The rats acclimatised to their
new conditions for four weeks before the beginning
of the study.
The experimental procedures were carried out
in accordance with the guidelines of the European
Community, and local laws and policies and were
approved by the Latvian Animal Protection Ethical Committee of the Food and Veterinary Service,
Riga, Latvia.
All experimental procedures and analyses were
performed by a person blinded to the treatment
groups.
Treatment and experimental protocol
Systolic blood pressure was measured in conscious
SHR rats at the beginning of the study using an
ML125 Non-Invasive Blood Pressure Controller
connected to a PowerLab8/30 system (ADInstruments, Chalgrove, UK) and a PC. Afterwards,
the experimental animals were divided into two
groups so that the average systolic blood pressure
in both groups was similar. The animals in the first
experimental group received magnesium nitrate
for four weeks at a dose of 50 mg/kg together with
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R. VILSKERSTS, ET AL.
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purified water, while the rats in the second group
(control group) received purified water alone. The
dosage of magnesium nitrate was confirmed by
measuring the consumption of drinking water
every two days and adjusting the concentration of the supplemented substance. The average
concentration of magnesium nitrate in the purified water during the study was 0.5 mg/mL. After
four weeks of treatment, the systolic blood pressure was measured in conscious rats from both
groups. Twenty-four hours after the measurement of the systolic pressure, the experimental
animals were anesthetised with sodium pentobarbital at a dose of 60 mg/kg. After the onset of
anaesthesia, the animals were put in a decubitus position and the chest was shaved. During the
echocardiographic procedure, the rats were allowed to breathe spontaneously. M-mode tracings
of the left ventricle were recorded at the papillary muscle level using an iE33 ultrasonograph
equipped with a linear L15-7io transducer (Philips
Healthcare, Andover, USA). After the echocardiographic parameters were recorded, heparin
(1 IU/g i.p.) was administered. Afterwards, the
chest was opened, the heart was isolated to perform the experimental heart infarction ex vivo,
and the aorta was excised to test the vascular
reactivity. Blood (∼5 mL) was collected in heparincontaining test tubes and centrifuged at 3000
rpm for 10 min at 4◦ C. The plasma obtained
was used for the quantification of nitrates and
nitrites.
Organ chamber experiments
Vascular reactivity in aortic rings was examined
in organ bath experiments as described previously
[21]. In brief, the excised thoracic aorta was
immersed in ice-cold Krebs-Henseleit (K-H) buffer solution and cleaned of fatty and connective
tissue. The aorta was cut into 3- to 4-mm-long
aortic rings that were suspended between two
stainless steel hooks in a 20 mL organ bath filled
with the K-H buffer solution. The bathing solution was continuously bubbled with 95% O2 and
5% CO2 and maintained at 37◦ C (pH of 7.3-7.5).
The passive tension was set to 20 mN. After a
period of equilibration (1 h), the maximal contractile function was assessed by the application of
60 mM KCl. The aortic rings were then precontracted to 60-80% of their maximum with
18
phenylephrine, and the cumulative response to
acetylcholine (10-10 -10-5 M) was assessed. In addition, to test vascular smooth muscle function,
the aortic rings were precontracted to the same
level as in the previous experimental setup, and
the cumulative response to SNP (10-10 -10-5 M)
was assessed. The relaxation of the aortic rings
in response to acetylcholine or SNP was expressed as a percentage of the phenylephrine-induced
constriction.
Experimental heart infarction ex vivo
The infarction study was performed according
to the Langendorff technique as described previously with slight modifications [22]. The hearts
were perfused in retrograde with an oxygenated
K-H buffer solution via the aorta at a constant
pressure of 60 mmHg. A water-ethanol mixture
(1:1)-filled balloon, connected to a physiological
pressure transducer (ADInstruments, Chalgrove,
UK) was inserted into the left ventricle, and
the baseline end-diastolic pressure was set between 5 and 10 mmHg. The heart rate, left
ventricle-developed pressure (LVDP), contractility, and relaxation were recorded continuously
using the PowerLab8/30 system from ADInstruments. Coronary flow was measured using an
ultrasound flow detector system connected to a
PowerLab8/30. A 4-0 coated, braided silk suture
(Sofsilk; Syneture, Dublin, Ireland) was passed
under the left anterior descending coronary artery
and threaded through a small plastic tube to permit reversible occlusion of the coronary artery. The
hearts were allowed to acclimatise for 20 minutes,
and the occlusion was performed for 30 minutes by
constricting the threads through the plastic tube.
The reperfusion was achieved by releasing the
threads. At the end of the 120-minute reperfusion,
the amount of necrotic myocardium was quantified as described previously [23]. The infarct size
was expressed as the percentage of necrosis in the
risk zone.
Quantification of magnesium, nitrate
and nitrite ions in blood plasma
The concentration of magnesium ions in plasma
samples was measured in an accredited diagnostic
laboratory (http://www.egl.lv), using automated
diagnostic equipment.
Magnesium nitrate attenuates blood pressure rise
Statistical analysis
The results were expressed as the mean ± SEM.
The Kolmogorov–Smirnov test was used to test the
distribution of the results obtained. Because the
data were normally distributed, the significance
of the differences between the mean values was
evaluated using parametric tests. Thus, the differences between the means were evaluated using
a two-tailed t-test, and p values of less than 0.05
were considered significant.
Results
150
**
Nitrates in plasma, µM
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Before the nitrates and nitrites were measured
in the plasma, it was filtered through Amicon®
Ultra 10 kDa centrifugal filter devices to separate
out the macromolecules. The nitrates and nitrites
were quantified in the filtered plasma using commercially available kits for the measurement of
nitrates and nitrites (Nitrate/Nitrite Fluorometric Assay Kit, Cayman Chemical Company, Ann
Arbor, USA), according to the manufacturer’s instructions.
100
50
0
Control
Magnesium
nitrate
Figure 1. Plasma concentration of nitrates in the
control group animals and in the animals receiving magnesium nitrate at a dose of 50 mg/kg.
Treatment with magnesium nitrate statistically
significantly increased the plasma level of nitrate.
The data are shown as the mean ± SEM
from seven to nine animals; **p<0.01, Student’s
t-test.
Excluded animals
During the administration period, two experimental animals from the magnesium nitrate receiving
group died for unknown reasons. The lethality in
magnesium group was apparently not due to the
administration of magnesium nitrate, as weight
increase in both groups was similar and rats from
magnesium nitrate group did not show any sign of
sickness or suffering.
Plasma levels of magnesium, nitrate and
nitrite ions
Administration of magnesium nitrate at the dose
of 50 mg/kg did not change the concentration
of magnesium ions in plasma. The magnesium ion concentrations in control and treated
group animals were 0.76 ± 0.05 mmol/L and
0.72 ± 0.01 mmol/L, respectively.
As shown in figure 1, the basal concentration
of nitrates in the blood plasma from the control
group animals was 62 ± 8 ␮mol/L. The administration of magnesium nitrate at a dose of 50 mg daily
for four weeks increased the level of nitrate in the
blood plasma to 111 ± 11 ␮mol/L (p<0.01). The
concentration of nitrite in the plasma was below
the detection level of the kit (<30 nM).
Effect of magnesium nitrate
supplementation on blood pressure
Before the beginning of the treatment, the average blood pressure in the control group rats was
168 ± 5 mmHg, and in the magnesium nitratetreated group animals the average blood pressure
was 172 ± 3 mmHg. After the four-week treatment
period, the average blood pressure in the control
group was 188 ± 6 mmHg, but in the magnesium
nitrate-treated group, the average blood pressure
was 177 ± 3 mmHg (figure 2A). We did not observe
any statistically significant difference between the
mean values for the systolic blood pressure of both
groups after the four-week treatment; even so,
the increase in blood pressure in the magnesium
nitrate-treated group was significantly (p = 0.02)
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R. VILSKERSTS, ET AL.
B
Changes in systolic pressure, mmHg
Systolic blood pressure, mmHg
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A
200
160
120
80
40
0
Control
30
20
*
10
0
Magnesium
nitrate
Control
Before treatment
After treatment
Magnesium
nitrate
Figure 2. Systolic blood pressure in the SHR male rats before and after the four-week treatment with
magnesium nitrate (A); alterations in systolic blood pressure (B). The administration of magnesium
nitrate for four weeks did not induce statistically significant changes in the systolic pressure. However,
the treatment with magnesium nitrate significantly delayed the increase in the systolic blood pressure.
The data are shown as the mean ± SEM from seven to nine animals; *p<0.05, Student’s t-test.
lower (figure 2B). The systolic pressure rose by
21 ± 3 mmHg and 6 ± 4 mmHg in the control and
magnesium nitrate-treated group, respectively.
Effect of magnesium nitrate
supplementation on echocardiographic
parameters
The treatment with magnesium nitrate at a dose
of 50 mg/kg did not influence the echocardiographic parameters of the heart, and there were
no statistically significant differences between
the echocardiographic parameters, including the
interventricular septal thickness at end-diastole,
left ventricular posterior wall thickness at enddiastole, left ventricular internal dimension at
end-diastole, left ventricular ejection fraction, left
ventricular fractional shortening, and the heart to
body mass index of the rats from both groups.
Effect of magnesium nitrate
supplementation on vascular reactivity
As can be observed in figure 3A, the fourweek treatment with magnesium nitrate had no
20
influence on the endothelium-dependent vasodilatation in the isolated thoracic aortic rings. The
maximal relaxation observed in the isolated aortic
rings was ∼50-60% of the Phe-induced contraction. In addition, the treatment with magnesium
nitrate did not influence the reactivity of the vascular rings to SNP (figure 3B).
Effect of magnesium nitrate
supplementation on infarct size
The cardioprotective effect of the administration
of magnesium nitrate was studied in the experimental heart infarction model ex vivo. As can
be observed in figure 4A, there was no difference
between the mean values of the area-at-risk between the groups. The average area-at-risk was
from 55 to 60% of the left ventricle. The analysis of the stained heart slices revealed that
there was no statistically significant difference
between the sizes of the heart infarct. The average infarction size was 33 ± 5 in the control
group and 40 ± 5% in the magnesium nitrate
group (figure 4B). The analyses of the heart rate,
LVDP, contractility, relaxation and coronary flow
Magnesium nitrate attenuates blood pressure rise
20
0
-10
-9
-8
-7
-6
-5
-20
-40
-60
-80
Relaxation, % of Phe contraction
Relaxation, % of Phe contraction
B
ACh, lg(c)
SNP, lg(c)
20
0
-10
-9
-8
-7
-6
-5
-20
-40
-60
-80
-100
Magnesium nitrate
Control
Figure 3. Effects of magnesium administration on endothelium-dependent (A) and endotheliumindependent (B) vasorelaxation. The treatment with magnesium nitrate for four weeks did not
influence endothelium-dependent or endothelium-independent relaxation in the SHR rats. The data
are shown as the mean ± SEM from seven to nine animals.
A
B
50
70
60
Infarction, % of area at risk
Area at risk, % of left ventricle
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A
50
40
30
20
10
0
40
30
20
10
0
Control
Magnesium
nitrate
Control
Magnesium
nitrate
Figure 4. Effects of magnesium nitrate treatment on infarct size in an experimental heart infarction
model ex vivo. The size of the area at risk (A) and the size of the infarction (B) in the experimental
model of heart infarction ex vivo. The administration of magnesium nitrate at a dose of 50 mg/kg for
four weeks had no effect on the infarct size. The data are shown as the mean ± SEM from seven to
nine animals.
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R. VILSKERSTS, ET AL.
during the experiment revealed that there were no
differences between the experimental and control
groups.
Discussion
Copyright © 2017 John Libbey Eurotext. Téléchargé par un robot venant de 88.99.165.207 le 04/05/2017.
The results of the present study demonstrate that
the administration of magnesium nitrate at a
dose of 50 mg/kg for four weeks increased the
nitrate concentration in the plasma and, at the
same time, significantly attenuated the increase
in the systolic blood pressure in hypertensive SHR
rats. In addition, the four-week treatment with
magnesium nitrate had no effect on the altered
vasoreaction, heart function or size of the heart
infarction.
The effects of the treatment with magnesium
and nitrate/nitrite separately on the development
of hypertension in SHR rats have been studied
before [8, 14]. In comparison with previously
published data, in which treatment with magnesium ions alone was used [14], we used a much
shorter treatment period (only 4 weeks), and SHR
rats with more severe hypertension (figure 2A),
which has been shown to limit the hypotensive
action of the magnesium administration [14].
Nevertheless, a statistically significant attenuation of the increase in systolic blood pressure was
observed (figure 2B). Thus, peroral administration of magnesium nitrate could be an effective
approach to attenuate the rise in blood pressure,
even in cases where elevated blood pressure has
been persistent for longer time periods.
Recent data have demonstrated that an intravenous bolus administration of nitrite, dosedependently lowered the blood pressure in SHR
rats [8], and the peroral administration of nitrates
to rats with unilateral nephrectomy, which were
fed on a high salt diet, dose-dependently lowered
the blood pressure and simultaneously increased the concentration of nitrates in plasma [7].
The analysis of the plasma samples from our
experimental animals revealed that rats receiving peroral magnesium nitrate had increased
plasma nitrate levels (figure 1); however, there
was no significant correlation between the plasma
concentration of nitrates and the changes in the
systolic blood pressure (data not shown). Moreover, it has been shown that supplementation with
magnesium ions also decreases elevated blood
pressure [13, 14]. Analysis of plasma samples
22
revealed that there was no difference between
magnesium ion concentrations in plasma from
animals from both groups. Magnesium ions are
mainly found intracellularly and only ∼0.3% of
the total magnesium pool is present in the serum,
the serum concentration usually does not reflect
the real magnesium pool in the tissues [13],
and additional supplementation will not alter the
concentration of magnesium ions in the plasma.
Nitrate/nitrite administration, and thus increased levels of both anions, is associated with
vasoprotective effects [9, 11]. In the SHR rat
model, endothelial dysfunction is characterised by unaltered nitric oxide synthesis, and
the acetylcholine-induced endothelial synthesis
of prostacyclines and prostaglandins induces
vasoconstriction by overpowering nitric oxide
relaxation [24]. Thus, the administration of additional nitrates or nitrites should not attenuate the
development of endothelial dysfunction by providing additional nitric oxide. However, a long-term
blood pressure decrease may inhibit the development of endothelial dysfunction, as it has been
shown that the level of vasoconstriction correlates
with the age of the SHR rats and the severity
of hypertension [24]. There was no difference in
the reactivity of the aortic rings to acetylcholine
or SNP between the treated and untreated animals, which is most likely due to the relatively
short treatment period. However, in an experimental model with a different mechanism for the
development of endothelial dysfunction, longer
administration or earlier onset of the treatment
with magnesium nitrate could also attenuate the
development of endothelial dysfunction.
The results from a previous study have shown
that the administration of nitrates protects
the myocardium from ischemia/reperfusion induced damage in healthy animals [10]. Recently
Fantinelli et al. demonstrated that the heart tissues of SHR rats at the hypertensive stage are
more susceptible to ischemia-reperfusion injury
than the heart tissues of their healthy counterparts [25]. In our experimental setup, we used
experimental animals with severe hypertension
(figure 2A): the treatment with magnesium nitrate
did not reduce the infarct size compared with the
untreated rat group. Although the substances that
demonstrate cardioprotective effects in healthy
animals could be cardioprotective in unhealthy
counterparts [25, 26], it has been shown that the
hypertension in SHR rats can blunt the effects of
post-conditioning [27] as well as pre-conditioning
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Magnesium nitrate attenuates blood pressure rise
in older SHR rats [28]. Thus, the hypertension
alters the activity and/or expression of proteins
that are involved in cardioprotection, and if
these proteins are involved in the cardioprotective action of the nitrates and nitrites, then the
cardioprotective activity of both anions could be
blunted.
In addition, a study published by Bryan et al.,
[10] showed that administration of nitrates protected heart against ischemia/reperfusion injury
and increased the concentration of nitrites in
plasma. It has been demonstrated that nitrites,
via different molecular pathways, induce protective effects in tissues [29, 30]. In our experimental
set-up, no increase in nitrites in the plasma
of treated animals was observed; consequently,
mean infarct size in both groups was similar.
In conclusion, the results from the present
study demonstrate that the administration of
magnesium nitrate attenuates the increase in
systolic blood pressure after a relatively short
administration period. However, a longer period
of administration or an earlier onset of treatment might be needed to delay the development
of complications due to hypertension such as
hypertrophy of the left ventricle and altered vasoreactivity.
Disclosure
5. Siervo M, Lara J, Ogbonmwan I, Mathers JC. Inorganic nitrate and beetroot juice supplementation
reduces blood pressure in adults: a systematic review and meta-analysis. J Nutr 2013; 143:
818-26.
6. Bryan NS, Alexander DD, Coughlin JR, Milkowski
AL, Boffetta P. Ingested nitrate and nitrite and stomach cancer risk: an updated review. Food Chem
Toxicol 2012; 50: 3646-65.
7. Carlstrom M, Persson AE, Larsson E, Hezel M,
Scheffer PG, Teerlink T, Weitzberg E, Lundberg JO.
Dietary nitrate attenuates oxidative stress, prevents
cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension. Cardiovasc Res
2011; 89: 574-85.
8. Ghosh SM, Kapil V, Fuentes-Calvo I, Bubb KJ, Pearl
V, Milsom AB, Khambata R, Maleki-Toyserkani S,
Yousuf M, Benjamin N, Webb AJ, Caulfield MJ,
Hobbs AJ, Ahluwalia A. Enhanced vasodilator activity of nitrite in hypertension: critical role for
erythrocytic xanthine oxidoreductase and translational potential. Hypertension 2013; 61: 1091-102.
9. Webb AJ, Patel N, Loukogeorgakis S, Okorie M,
Aboud Z, Misra S, Rashid R, Miall P, Deanfield J,
Benjamin N, MacAllister R, Hobbs AJ, Ahluwalia A.
Acute blood pressure lowering, vasoprotective, and
antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension 2008; 51: 784-90.
10. Bryan NS, Calvert JW, Elrod JW, Gundewar S,
Ji SY, Lefer DJ. Dietary nitrite supplementation
protects against myocardial ischemia-reperfusion
injury. Proc Natl Acad Sci U S A 2007; 104: 19144-9.
Financial support: this study was supported by the
Latvian State Research Program BIOMEDICINE
and Rigas Stradins University research project
No. RSU ZP 09/2013. Conflict of interest: none.
11. Alef MJ, Vallabhaneni R, Carchman E, Morris
Jr. SM, Shiva S, Wang Y, Kelley EE, Tarpey
MM, Gladwin MT, Tzeng E, Zuckerbraun BS.
Nitrite-generated NO circumvents dysregulated
arginine/NOS signaling to protect against intimal
hyperplasia in Sprague-Dawley rats. J Clin Invest
2011; 121: 1646-56.
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