(Hypertension. 2001;37:554.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Oxidative Stress in a Rat Model of Obesity-Induced Hypertension
From the Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk.
Correspondence to Anca Dobrian, PhD, Eastern Virginia Medical School, Department of Physiological Sciences, 700 W Olney Rd, Norfolk, VA 23507. E-mail dobriaad{at}evms.edu
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Abstract |
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The mechanisms underlying the development of hypertension in obesity are not yet fully understood. We recently reported the development of hypertension in a rat model of diet-induced obesity. When Sprague-Dawley rats (n=60) are fed a moderately high fat diet (32 kcal% fat) for 10 to 16 weeks, approximately half of them develop obesity (obesity-prone [OP] group) and mild hypertension (158±3.4 mm Hg systolic pressure), whereas the other half (obesity-resistant [OR] group) maintains a body weight equivalent to that of a low fat control group and is normotensive (135.8±3.8 mm Hg). We examined the potential role of oxidative stress in the development of hypertension in this model. Lipid peroxides measured as thiobarbituric acid–reactive substances showed a significant increase in the LDL fraction of OP rats (2.8±0.32 nmol malondialdehyde/mg protein) compared with OR and control rats (0.9±0.3 nmol malondialdehyde/mg protein). Also, aortic and kidney thiobarbituric acid–reactive substances showed a significant (3- and 5- fold) increase in OP rats after 16 weeks of diet. In addition, superoxide generation by aortic rings, measured by lucigenin luminescence, showed a 2-fold increase in the OP group compared with both the OR and control groups. In addition, free isoprostane excretion and nitrotyrosine in the kidney showed an increase in OP rats only. The urine and plasma nitrate/nitrite measured by the LDH method showed a 1.8-fold decrease in OP rats compared with OR rats. However, endothelial NO synthase expression in the kidney cortex and medulla assessed by reverse transcriptase–polymerase chain reaction showed a strong increase in the OP rats versus OR and control rats (endothelial NO synthase/ß-actin ratio 1.3±0.04 in OP rats versus 0.44±0.02 in OR rats), suggesting a possible shift toward superoxide production by the enzyme. Collectively, the data show a decreased NO bioavailability in OP animals that is due in part to the increased oxidative stress.
Key Words: diet • nitric oxide • obesity • oxidative stress • kidney • lipids
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Introduction |
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Obesity is an important contributor to essential hypertension in humans. Data from the Framingham Heart Study suggest that
78% of essential
hypertension in men and 65% in women can be directly attributed to
obesity.1 However, the
mechanisms that link obesity with high blood pressure (BP) have not
been fully elucidated. There are data that indicate increased oxidative
stress in human essential
hypertension2 3 as
well as in obese hypertensive
patients.4 Also, the
involvement of the superoxide radical in BP regulation has been
reported for several animal models of hypertension, such as the
spontaneously hypertensive
rat,5 6 Dahl
rat,7 and
angiotensin II–infused
rat.8 Romero’s group (Haas et
al9 and Reckelhoff et
al10 ) has recently reported
that subpressor doses of angiotensin II are able to
generate oxidative stress in pigs and rats, which, in turn, is able to
induce chronic elevations in BP. The increase in superoxide
production in hypertension has been shown to have an impact on
the production and bioavailability of endogenous
vascular NO. The ability of NO to interact quickly with superoxide,
leading to the formation of
peroxynitrite,11 is a
probable cause for the impairment of
endothelium-dependent relaxation in rats after the
experimental elevation of
BP12 13 or in
patients with essential
hypertension.14 Much less is
known about the involvement of oxidative stress in obesity-induced
hypertension. The only animal studies concern obese Zucker rats, a
genetic model of obesity that also displays type II diabetes but
develops hypertension only when fed a high salt diet. In this model,
endothelium-dependent vasodilation is not
affected,15 unless a
pro-oxidant prodiabetic challenge is induced in
vivo.16 Also, the
endothelial hyperreactivity in Zucker rats can be
reversed by vitamin E.17
However, in this rat model, one cannot rule out the confounding effect
of type II diabetes on the development of hypertension and its relation
to oxidative stress. We have recently reported that diet-induced
obesity in Sprague-Dawley rats also leads to the development of mild to
moderate hypertension.18 We
hypothesize that oxidative stress might be a common link that underlies
both obesity and hypertension. Therefore, we investigated the oxidative
status in this model and its effects on renal function. Also, we
consider this model particularly useful in assessing the role of
hyperlipidemia, which is known to be involved in the
generation of free radicals19
and increased vascular
reactivity,20 and diet in a
direct causal relationship with hypertension, obesity, and oxidative
stress. |
Methods |
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Animals
All procedures involving animals were approved by the Institutional Animal Care and Use Committee of Eastern Virginia Medical School. Thirty-two male Sprague-Dawley rats (300 to 350 g) were randomly selected to be fed a moderately high fat (MHF) diet (32 kcal% as fat, Research Diets), and 8 rats (control group) were fed a purified low fat diet (10.6 kcal% as fat, Research Diets) for 16 weeks. Food and water were provided ad libitum throughout the experiment. Body weights (BWs) and lengths were measured initially and then weekly together with food intake. Rats fed the MHF diet diverged into distinct groups based on BW gains. The assignment of rats into obesity-prone (OP, n=8) and obesity-resistant (OR, n=8) groups was performed by construction of BW gain histograms at the end of the study for MHF and low fat diet groups, respectively. This gave a bimodal distribution for the former and a unimodal distribution for the latter, as has been previously described.21 22 The result was confirmed by Pearson
2
analysis of MHF diet–fed rats. OR rats were defined as those
with weight gains equal to or less than the heaviest control rats, and
OP rats were defined as those with greater weight
gains.21 At the end of the
study, the rats were decapitated, and trunk blood was collected in
EDTA-coated tubes. Plasma was immediately separated by
centrifugation and used for different assays. Thoracic
aorta, kidney, and fat depots were harvested, weighed, and either used
immediately or snap-frozen in liquid nitrogen. The week before
euthanasia, the rats were transferred to metabolic cages,
and 24-hour urine samples were collected on ice and used to assess
renal excretory function, nitrate/nitrite content, and free
F2
-isoprostanes.
Systolic BP
The onset and development of hypertension were
assessed by using the tail-cuff method with a Narco Biosystems
Electro-Sphygmomanometer. BP was measured with the animals under
conscious conditions at the beginning of the experiment and at 1, 5, 8,
10, and 16 weeks of the diet. The average of 3 pressure readings was
recorded for each measurement.
Assessment of Oxidative Stress
Superoxide Anion Production
Superoxide anion production was measured in
isolated aortic rings with use of a method previously
described.23 Briefly, 5-mm
aortic rings were preincubated in Krebs-bicarbonate buffer, at 37°C,
for 30 minutes and then transferred to a cocktail containing 25
µmol/L lucigenin and immediately measured, every 2 minutes, for a
total of 15 minutes, with use of a scintillation counter set in the
out-of-coincidence mode. The readings were plotted, and the area under
the curve was integrated. Results were normalized per milligram DNA,
which was measured with the use of Hoechst 33258 dye, as
described.24 The specificity
of the reaction was tested by the ability of 50 U/mL SOD to quench the
chemiluminescence at the end of the measurement.
Free 8-Isoprostane
F2
Isoprostanes were measured by enzyme immunoassay
(EIA) with use of a kit from Cayman Chemicals. Urine collected in
metabolic cages over a 24-hour period was supplemented with
0.05% butylated hydroxytoluene and spiked with
[3H]8-isoprostane (NEN). The samples (1
mL) were passed on an affinity column (Cayman Chemicals), and only the
free isoprostanes were eluted with use of 95% methanol. The eluate was
evaporated to dryness under a stream of N2, and
the pellet was resuspended in a 1-mL assay buffer. Each sample was
assayed in duplicate at 2 different dilutions and corrected for the
individual recovery of [3H]8-isoprostane,
and the results were averaged.
Lipid Peroxides
Lipid peroxidation in the LDL fraction and tissues
(thoracic aorta and kidney) was determined by measuring
spectrophotometrically the amount of malondialdehyde, according to
Fogelman et al.25 LDL was
dialyzed against Tris-HCl buffer, supplemented with 0.01% EDTA and
0.33 mmol/L butylated hydroxytoluene, and assayed within 48 hours
on isolation. The tissues were collected on ice, washed in 0.9% NaCl,
and immediately homogenized in 20 mmol/L Tris-HCl (pH
7.4) with 5 mmol/L butylated
hydroxytoluene.26
Nitrate/Nitrite
Nitrate/nitrite was assayed in plasma and urine
(diluted 1:50 in PBS) by use of an LDH colorimetric
method with a kit from Cayman Chemicals.
eNOS mRNA Expression
Endothelial NO synthase (eNOS) mRNA
expression was measured by semiquantitative reverse transcriptase
(RT)–polymerase chain reaction (PCR) with the use of ß-actin as a
housekeeping gene. Total RNA was extracted by use of Trizol reagent
(GIBCO), according to the manufacturer’s protocol. RNA (0.5 to 1 µg)
was reverse-transcribed at 42°C, for 45 minutes, with the use of
avian myeloblastosis virus RT and then amplified for eNOS by use of the
"touch-down" PCR that is optimized to amplify low abundant mRNA
copies.27 The method includes
a highly specific preamplification step, starting at a 70°C annealing
temperature, before the 30-cycle PCR at 55°C. The primers used for
eNOS were as follows: 5'-ACGCCTCTTTTCCCTCTCTA-3' (sense) and
5'-TGGCA-CAGTCCCTTATGGTA-3' (antisense). The length of the
product was 237 bp. For ß-actin, the samples were amplified for
25 cycles only, at 55°C annealing temperature. The PCR products
were separated on a 1.5% agarose gel and stained with ethidium
bromide, and the intensity of the bands was measured by densitometry
with use of an EagleEye System (Stratagene) and SigmaGel Software
(Jandel Scientific).
Nitrotyrosine Assay
Kidney samples were immediately
homogenized in 0.1 mol/L phosphate buffer supplemented with
1 mmol/L EDTA and 10 µmol/L indomethacin.
Homogenates were analyzed for nitrotyrosine content
by use of an enzyme immunoassay with a monoclonal antibody for
nitrotyrosine and reagents from Cayman Chemicals. The samples were
assayed in duplicate at 2 different dilutions, and the results were
averaged. The plate was read at 405 nm, and the concentration was
calculated by using a standard curve for nitrotyrosine in a 2- to
250-ng/mL range. The data were normalized to the protein content of the
tissue sample.
Other Assays
Creatinine and protein in urine were
assayed with colorimetric kits from Sigma, and urine
albumin was assayed with an EIA kit from Cayman Chemicals.
Plasma renin activity (PRA) was measured with a kit from DiaSorin Inc,
with use of 125I-angiotensin I (ATI)
generation.
Statistical Analysis
Data are shown as mean±SE. To determine the
significance between different groups, 1-way ANOVA was performed,
followed by the Tukey post hoc test. A value of
P<0.05 was considered
statistically significant.
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Results |
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BW, BP, and PRA
The BWs for OP, OR, and control rats were measured weekly and did not differ significantly at the beginning of the study (Table 1). After 16 weeks of diet, both the BW and the BW gain in the OP group were significantly higher than those in the OR and control groups (Table 1). Results also show that all 3 fat depots measured, as well as the adiposity index (the equivalent of the body mass index for humans), were all significantly higher in the OP rats compared with OR and control rats, reflecting the increased body fat content (Table 1). Systolic BP measured in the conscious rats at the beginning of the diet indicated an average of 121±3.1 mm Hg. Starting with week 8, the OP rats had a higher BP compared with both control and OR rats (Figure 1). The increase in BP after week 8 was minimal for OP rats, whereas the BP of OR and control rats remained unchanged until the end of the study (Figure 1). With a systolic BP averaging 157.8 mm Hg, the OP group was considered to be mildly to moderately hypertensive, whereas the OR rats exhibited only borderline hypertension (Table 2). The increase in BP was paralleled by an increase in heart rate, which became significantly different after 16 weeks of diet in the OP group compared with the OR and control groups (Table 2). Also, in accordance with our previous data,18 OP rats showed an activation of the renin-angiotensin system, as reflected by a doubling in PRA, compared with OR and control rats (Table 2).
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Oxidative Stress in OP, OR, and Control
Rats
The ability of isolated aortic rings from OP, OR, and
control rats to generate superoxide anion as measured by lucigenin
chemiluminescence is illustrated in
Figure 2A. The results showed a 1.8-fold increase in
superoxide production by the thoracic aortas from OP rats
compared with both OR and control rats, suggesting an increased in vivo
production of the radical. Also, the excretion of free
8-isoprostane F2, measured by EIA in 24-hour
urine samples, indicated a 3-fold increase, to 22.3±2.9 ng over 24
hours, compared with both OR and control rats
(Figure 2B). Together, superoxide generation and isoprostane
excretion suggest an increase in local and systemic oxidative stress in
the OP rats. In accordance with these data, lipid peroxidation in the
LDL fraction and thoracic aorta was elevated by 3-fold in the OP
group, whereas the values for thiobarbituric acid–reactive substances
(TBARS) were increased 7-fold in the kidney samples of the OP rats
compared with both OR and control rats
(Figure 3A). The augmentation in lipid peroxides mirrors the
increased ability of the thoracic aorta of OP rats to generate
superoxide anions.
Figure 3B illustrates the modest but still significant
increase in the nitrotyrosine content of the OP rat kidney samples
compared with OR and control rat samples. The OP rats had an average
amount of 12.8±2.3 ng nitrotyrosine/mg tissue protein compared with
9.1±0.87 and 8.4±0.12 ng nitrotyrosine/mg tissue protein for OR and
control rats, respectively. The elevated amount of nitrotyrosine in the
OP rats may reflect the increased interaction between superoxide and NO
in the obese hypertensive animals.
Figure 4 illustrates a 1.8-fold decrease in plasma and urine
nitrate/nitrite content, suggesting a decreased production or
bioavailability of NO in OP rats compared with OR and control rats. The
expression of eNOS mRNA normalized to ß-actin expression and
representative micrographs of the gels are shown in
Figure 5. A substantial increase in eNOS expression seems to
occur in the OP rats and occurs to a much lower extent in the OR rats
compared with control rats. This rules out the role of the high fat
diet in the upregulation of eNOS expression in this animal model. The
data so far pointed toward a decreased NO availability in the OP rats
that was due, at least in part, to the increased superoxide
production. Finally, we measured some parameters to
assess the renal excretory function, as shown in
Table 2. Except for the creatinine values,
which are moderately increased in both OP and OR rats, the protein,
albumin, and Na+ excretion are all
within the normal values reported for rats, indicating a normal kidney
excretory function for all 3 groups
(Table 2).
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Discussion |
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This model of diet-induced obesity, extensively described previously,28 29 developed hypertension subsequent to the development of visceral adiposity,18 suggesting a role for metabolic factors associated with obesity in the development of hypertension. In a recent study,18 we showed that in both OP and OR rats there is increased peroxidation in the LDL fraction. The present study aimed to extend the data regarding oxidative stress in this model. Our data show that in OP rats, but not in OR or control rats, there is a 2-fold increase in the PRA. This indirectly suggests that the circulating levels of angiotensin II are increased in obese hypertensive animals. It is extensively reported that angiotensin II in either high doses8 12 or subpressor doses10 is able to induce oxidative stress. One way is through NADH/NADPH activation, which is believed to be the major source of superoxide anion in the arterial wall.12 Therefore, it is reasonable to assume that angiotensin II is likely to be involved in the increased generation of superoxide radicals by the aortic rings of OP rats. However, the cause for the increased PRA is more difficult to explain. One possible explanation might be related to the sympathetic activation in OP rats. Increased plasma norepinephrine response to intravenous glucose was previously reported by Levin and colleagues28 30 in OP rats. Also, our results showing an increased heart rate in OP rats may reflect a certain degree of sympathetic activation. As previously reported,18 the lipid peroxides, measured as TBARS, were increased in the LDL fraction and thoracic aorta of OP rats compared with OR and control rats. In the present study, we showed the same
3-fold increase in both LDL
and aortic TBARS and, in addition, an even higher elevation of
7-fold in the kidney samples of OP rats compared with OR and control
rats. This elevation is observed without a significant increase in
total lipid content of the kidney (data not shown), suggesting that
only the peroxidation state, and not the amount of lipids, varies in
the kidneys of OP rats. A more accurate method to assess oxidative
stress (and in particular, lipid oxidation) is the formation of
8-isoprostaglandin
F2,31
a stable product generated from arachidonic acid in
phospholipids and subsequently released in free
form.32 Our data showed that
the increase in kidney TBARS is paralleled by a 3.5-fold elevation
of the free isoprostanes in urine. The level of 24-hour urine
isoprostanes presumably provides an integrated assessment of
isoprostane production with time and, because the lipids in
urine are negligible, is less subject to artifacts because of ex vivo
generation of isoprostanes.6
It is not yet clear whether the urinary isoprostanes are derived
exclusively by filtration from the circulation, by formation in the
kidney, or by a combination of both. Nevertheless, there is substantial
evidence indicating that isoprostanes are potent vasoconstrictors in
the aortic, renal, and pulmonary beds in
vitro.33 34 Of
particular importance is the observation that administration through
intrarenal infusion of low nanomolar concentrations of isoprostanes in
rats produces a potent renal vasoconstriction, reducing
glomerular filtration rate and renal blood
flow.35 Moreover, enhanced
isoprostane production was observed in spontaneously
hypertensive rats6 and in rats
infused with angiotensin
II.9 Also, an increased level
of isoprostanes was reported in hypercholesterolemic
pigs36 and in human
atherosclerotic plaques.37
However, in our model, hypercholesterolemia
does not seem to be the cause of the increased level of isoprostanes,
because in OR rats, which are hypercholesterolemic, the
isoprostanes are at the same levels as in control normolipidemic rats.
Apart from the increased production of vasoconstrictor
isoprostanes, in the plasma and urine of OP rats, the level of
nitrate/nitrite was decreased 1.8-fold, suggesting a reduced
production of NO compared with that in OR and control rats.
However, semiquantitative RT-PCR showed that eNOS in the thoracic
aorta, kidney cortex, and medulla was increased 8-fold in OP rats
compared with OR and control rats, suggesting the potential that more
NO could be generated in these animals. An increase in eNOS expression
was also recently reported in subcutaneous adipose tissues of obese
humans.38 There are several
possible explanations for the apparent discrepancy of the 2 results.
First, under certain conditions, eNOS can produce superoxide rather
than NO.39 This was mainly
noticed in hypercholesterolemia, in which a
tetrahydrobiopterin deficiency seems to be responsible for the
superoxide production by
eNOS,40 but also in other
pathological conditions, such as insulin
resistance.41 In our model,
hypercholesterolemia does not seem to have a
major role, because both OP and OR rats are
hypercholesterolemic, but only OP rats have increased
eNOS expression. Another possible explanation is the ability of
superoxide to quench NO, with the formation of the potent oxidant
peroxynitrite.11 One major
product of peroxynitrite attack on proteins is the nitration on the
3 position of tyrosine. Although other reactions can form
nitrotyrosine, the rates and yields of the alternative nitration
mechanisms seem to be rather small, and it is still considered a good
footprint left by peroxynitrite in tissues in
vivo.42 Our data showed that
there is a modest, although significant, increase in the nitrotyrosine
levels in the kidneys of OP rats compared with OR and control rats.
This result, together with the increase in superoxide
production and eNOS expression, may suggest that we indeed have
an increased formation of peroxynitrite in obese hypertensive animals
that reduces the NO bioavailability and hence may induce
vasoconstriction of the kidney vasculature. This adds to the potential
vasoconstrictor effect of the increased level of isoprostanes in OP
rats. Although peroxynitrite can also induce vasodilation (and hence
counteract, at least in part, the reduced NO bioavailability in certain
vascular areas), at high concentrations its damaging action is likely
to overcome the protective vasodilatory response. Moreover, Villa et
al43 have demonstrated that
under a broad range of concentrations, peroxynitrite may induce
tachyphylaxis to its own vasodilator action and may impair the response
to other vasodilators in coronary rat vessels. The apparent
reduction in NO bioavailability may also explain the increased level of
PRA in OP rats. Although the precise effect of NO on renin synthesis
and secretion is still a matter of controversy, several authors have
reported a significant increase in PRA in animals made hypertensive by
chronic NO
blockade.44 45
Also, the chronic infusion of
NG-nitro-L-arginine
methyl ester seems to activate both PRA and sympathetic
functions,46 which were also
reported to be elevated in the OP
rats.21 Additionally, our
data suggest that diet is not the critical factor in the evolution of
hypertension, inasmuch as both OP and OR rats are fed a similar MHF
diet, but only OP rats are hypertensive and have a significantly
increased adiposity index. Moreover,
hypercholesterolemia, which is manifest in both
the OP and OR rats, does not seem to have a crucial role in the
development of hypertension in this model. On the other hand, the
increased levels of circulating renin, and possibly
angiotensin II, seem to be related to the oxidative stress
measured in the model. Although we cannot conclude whether oxidative
stress is the cause or consequence of hypertension obesity, it seems
possible that it mediates the effect of angiotensin II on
BP regulation in this
model.
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Acknowledgments |
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This study was supported by National Institutes of Health grant HL-54810, a Grant-in-Aid from the American Heart Association, and a postdoctoral fellowship from the MidAtlantic Affiliate of the American Heart Association to Dr Dobrian.
Received October 25, 2000; first decision November 27, 2000; accepted December 11, 2000.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Kannel WB, Brand N, Skinner JJ Jr, Dawber TR, McNamara PM. The relation of adiposity to blood pressure and development of hypertension: the Framingham study. Ann Intern Med. 1967;67:48–59.
2. Russo C, Olivieri O, Girelli D, Faccini G, Zenari ML, Lombardi S, Corrocher R. Anti-oxidant status and lipid peroxidation in patients with essential hypertension. J Hypertens. 1998;16:1267–1271.[Medline] [Order article via Infotrieve]
3. Sagar S, Kallo IJ, Kaul N, Ganguly NK, Sharma BK. Oxygen free radicals in essential hypertension. Mol Cell Biochem. 1992;111:103–108.[Medline] [Order article via Infotrieve]
4. Van Gaal LF, Zhang A, Steijaert MM, De Leeuw IH. Human obesity: from lipid abnormalities to lipid oxidation. Int J Obes Relat Metab Disord. 1995;19(suppl 3):S21–S26.
5.
Suzuki H, Swei A,
Zweifach BW, Schmid-Schonbein GW. In vivo evidence for microvascular
oxidative stress in spontaneously hypertensive rats: hydroethidine
microfluorography.
Hypertension. 1995;25:1083–1089.
6.
Schnackenberg CG,
Wilcox CS. Two-week administration of tempol attenuates both
hypertension and renal excretion of 8-Iso prostaglandin
f2alpha. Hypertension. 1999;33:424–428.
7.
Swei A, Lacy F,
DeLano FA, Schmid-Schonbein GW. Oxidative stress in the Dahl
hypertensive rat. Hypertension. 1997;30:1628–1633.
8.
Laursen JB,
Rajagopalan S, Galis Z, Tarpey M, Freeman BA, Harrison DG. Role of
superoxide in angiotensin II–induced but not
catecholamine-induced hypertension.
Circulation. 1997;95:588–593.
9.
Haas JA, Krier JD,
Bolterman RJ, Juncos LA, Romero JC. Low-dose angiotensin II
increases free isoprostane levels in plasma.
Hypertension. 1999;34:983–986.
10.
Reckelhoff JF,
Zhang H, Srivastava K, Roberts LJ II, Morrow JD, Romero JC. Subpressor
doses of angiotensin II increase plasma F(2)-isoprostanes
in rats. Hypertension. 2000;35:476–479.
11. Squadrito GL, Pryor WA. The formation of peroxynitrite in vivo from nitric oxide and superoxide. Chem Biol Interact. 1995;96:203–206.[Medline] [Order article via Infotrieve]
12. Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest. 1996;97:1916–1923.[Medline] [Order article via Infotrieve]
13.
Grunfeld S,
Hamilton CA, Mesaros S, McClain SW, Dominiczak AF, Bohr DF, Malinski T.
Role of superoxide in the depressed nitric oxide production by
the endothelium of genetically hypertensive rats.
Hypertension. 1995;26:854–857.
14. Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990;323:22–27.[Abstract]
15.
Bohlen HG, Lash
JM. Endothelial-dependent vasodilation is preserved in
non-insulin-dependent Zucker fatty diabetic rats.
Am J Physiol. 1995;268:H2366–H2374.
16. Laight DW, Desai KM, Anggard EE, Carrier MJ. Endothelial dysfunction accompanies a pro-oxidant, pro-diabetic challenge in the insulin resistant, obese Zucker rat in vivo. Eur J Pharmacol. 2000;402:95–99.[Medline] [Order article via Infotrieve]
17. Andrews TJ, Laight DW, Anggard EE, Carrier MJ. Investigation of endothelial hyperreactivity in the obese Zucker rat in-situ: reversal by vitamin E. J Pharm Pharmacol. 2000;52:83–86.[Medline] [Order article via Infotrieve]
18.
Dobrian AD, Davies
MJ, Prewitt RL, Lauterio TJ. Development of hypertension in a rat model
of diet-induced obesity.
Hypertension. 2000;35:1009–1015.
19.
Ohara Y, Peterson
TE, Sayegh HS, Subramanian RR, Wilcox JN, Harrison DG. Dietary
correction of hypercholesterolemia in the
rabbit normalizes endothelial superoxide anion
production.
Circulation. 1995;92:898–903.
20. Jayakody RL, Senaratne MP, Thomson AB, Kappagoda CT. Cholesterol feeding impairs endothelium-dependent relaxation of rabbit aorta. Can J Physiol Pharmacol. 1985;63:1206–1209.[Medline] [Order article via Infotrieve]
21. Levin BE, Triscari J, Sullivan AC. Altered sympathetic activity during development of diet-induced obesity in rat. Am J Physiol. 1983;244:R347–R355.
22.
Lauterio TJ,
Barkan A, DeAngelo M, DeMott-Friberg R, Ramirez R. Plasma growth
hormone secretion is impaired in obesity-prone rats before onset of
diet-induced obesity. Am J
Physiol. 1998;275:E6–E11.
23. Gyllenhammar H. Lucigenin chemiluminescence in the assessment of neutrophil superoxide production. J Immunol Methods. 1987;97:209–213.[Medline] [Order article via Infotrieve]
24. Labarca C, Paigen K. A simple, rapid, and sensitive DNA assay procedure. Anal Biochem. 1980;102:344–352.[Medline] [Order article via Infotrieve]
25.
Fogelman AM,
Shechter I, Seager J, Hokom M, Child JS, Edwards PA. Malondialdehyde
alteration of low density lipoproteins leads to cholesteryl ester
accumulation in human monocyte-macrophages.
Proc Natl Acad Sci
U S A. 1980;77:2214–2218.
26. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95:351–358.[Medline] [Order article via Infotrieve]
27. Karet FE, Charnock-Jones DS, Harrison-Woolrych ML, O’Reilly G, Davenport AP, Smith SK. Quantification of mRNA in human tissue using fluorescent nested reverse- transcriptase polymerase chain reaction. Anal Biochem. 1994;220:384–390.[Medline] [Order article via Infotrieve]
28.
Levin BE, Triscari
J, Hogan S, Sullivan AC. Resistance to diet-induced obesity: food
intake, pancreatic sympathetic tone, and insulin.
Am J Physiol. 1987;252:R471–R478.
29. Lauterio TJ, Bond JP, Ulman EA. Development and characterization of a purified diet to identify obesity-susceptible and resistant rat populations. J Nutr. 1994;124:2172–2178.
30. Levin BE, Triscari J, Sullivan AC. Relationship between sympathetic activity and diet-induced obesity in two rat strains. Am J Physiol. 1983;245:R364–R371.
31.
Lawson JA, Rokach
J, FitzGerald GA. Isoprostanes: formation, analysis and use as
indices of lipid peroxidation in vivo.
J Biol Chem. 1999;274:24441–24444.
32. Roberts LJ II, Morrow JD. The generation and actions of isoprostanes. Biochim Biophys Acta. 1997;1345:121–135.[Medline] [Order article via Infotrieve]
33. Wagner RS, Weare C, Jin N, Mohler ER, Rhoades RA. Characterization of signal transduction events stimulated by 8-epi-prostaglandin(PG)F2 alpha in rat aortic rings. Prostaglandins. 1997;54:581–599.[Medline] [Order article via Infotrieve]
34. Kromer BM, Tippins JR. Coronary artery constriction by the isoprostane 8-epi prostaglandin F2 alpha. Br J Pharmacol. 1996;119:1276–1280.[Medline] [Order article via Infotrieve]
35. Takahashi K, Nammour TM, Fukunaga M, Ebert J, Morrow JD, Roberts LJ II, Hoover RL, Badr KF. Glomerular actions of a free radical-generated novel prostaglandin, 8-epi-prostaglandin F2 alpha, in the rat: evidence for interaction with thromboxane A2 receptors. J Clin Invest. 1992;90:136–141.
36.
Wilson SH, Best
PJ, Lerman LO, Holmes DR Jr, Richardson DM, Lerman A. Enhanced
coronary vasoconstriction to oxidative stress product,
8-epi-prostaglandinF2 alpha, in experimental
hypercholesterolemia.
Cardiovasc Res. 1999;44:601–607.
37. Pratico D, Iuliano L, Mauriello A, Spagnoli L, Lawson JA, Rokach J, Maclouf J, Violi F, FitzGerald GA. Localization of distinct F2-isoprostanes in human atherosclerotic lesions [published erratum appears in J Clin Invest.. 1997;100:2637]. J Clin Invest. 1997;100:2028–2034.
38.
Elizalde M, Ryden
M, van Harmelen V, Eneroth P, Gyllenhammar H, Holm C, Ramel S, Olund A,
Arner P, Andersson K. Expression of nitric oxide synthases in
subcutaneous adipose tissue of nonobese and obese humans.
J Lipid Res. 2000;41:1244–1251.
39. Stroes E, Hijmering M, van Zandvoort M, Wever R, Rabelink TJ, van Faassen EE. Origin of superoxide production by endothelial nitric oxide synthase. FEBS Lett. 1998;438:161–164.[Medline] [Order article via Infotrieve]
40.
Xia Y, Tsai AL,
Berka V, Zweier JL. Superoxide generation from
endothelial nitric-oxide synthase: a
Ca2+/calmodulin-dependent and
tetrahydrobiopterin regulatory process.
J Biol Chem. 1998;273:25804–25808.
41.
Shinozaki K,
Nishio Y, Okamura T, Yoshida Y, Maegawa H, Kojima H, Masada M, Toda N,
Kikkawa R, Kashiwagi A. Oral administration of tetrahydrobiopterin
prevents endothelial dysfunction and vascular oxidative
stress in the aortas of insulin-resistant rats.
Circ Res. 2000;87:566–573.
42. Ye YZ, Strong M, Huang ZQ, Beckman JS. Antibodies that recognize nitrotyrosine. Methods Enzymol. 1996;269:201–209.[Medline] [Order article via Infotrieve]
43.
Villa LM, Salas E,
Darley-Usmar VM, Radomski MW, Moncada S. Peroxynitrite induces both
vasodilatation and impaired vascular relaxation in the isolated
perfused rat heart. Proc Natl Acad Sci
U S A. 1994;91:12383–12387.
44.
Ribeiro MO,
Antunes E, de Nucci G, Lovisolo SM, Zatz R. Chronic inhibition of
nitric oxide synthesis: a new model of arterial
hypertension. Hypertension. 1992;20:298–303.
45.
Hu L, Manning RD
Jr, Brands MW. Long-term cardiovascular role of nitric
oxide in conscious rats.
Hypertension. 1994;23:185–194.
46. K-Laflamme A, Foucart S, Moreau P, Lambert C, Cardinal R, de Champlain J. Sympathetic functions in NG-nitro-L-arginine-methyl-ester-induced hypertension: modulation by the renin-angiotensin system. J Hypertens. 1998;16:63–76.[Medline] [Order article via Infotrieve]
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