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(Hypertension. 2001;37:781.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Long-Term Antioxidant Administration Attenuates Mineralocorticoid Hypertension and Renal Inflammatory Response
From the Departments of Physiology (R.C.W.) and Anatomy (W.D.H.) and the Vascular Biology Center (H.Z., J.D.C.), Medical College of Georgia, Augusta, Ga; Department of Physiology (R.A.B.), University of Michigan (Ann Arbor); and Department of Biology (D.M.), Fort Valley State University, Fort Valley, Ga.
Correspondence to Dr Richard A. Beswick, Department of Physiology, Medical College of Georgia, Augusta, GA 30912-3000. E-mail rbeswick{at}umich.edu
 |
Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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We previously reported increased monocyte/macrophage infiltration, reactive oxygen species accumulation, and nuclear factor-
B (NF-B)
activation in mineralocorticoid (deoxycorticosterone acetate [DOCA])
hypertensive rats. We tested the hypothesis that prolonged antioxidant
administration inhibits superoxide accumulation, lowers blood pressure,
and reduces NF-B activation in DOCA-salt hypertensive rats. DOCA
rats exhibited a significant increase in systolic blood
pressure compared with sham rats. Aortic rings from DOCA rats exhibited
increased superoxide
(O2-)
production compared with sham rats. In addition, the treatment
of DOCA rats with pyrrolidinedithiocarbamate (PDTC) or
4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (Tempol) caused a
significant decrease in systolic blood pressure and aortic
superoxide accumulation. Monocyte/macrophage infiltration was
also significantly decreased in DOCA rats treated with PDTC or Tempol
compared with untreated DOCA rats. NF-B–binding activity was
significantly greater in untreated DOCA rats than in either sham rats
or PDTC- or Tempol-treated DOCA rats. Also, DOCA rats treated with
Tempol exhibited no significant difference in NF-B–binding activity
compared with sham. These results suggest that antioxidants attenuate
systolic blood pressure, suppress renal NF-B–binding
activity, and partly alleviate renal monocyte/macrophage
infiltration in DOCA-salt hypertension.
Key Words: Tempol • pyrrolidinedithiocarbamate • hypertension, mineralocorticoid • nuclear factor-B • monocyte/macrophage
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Hypertension imparts an increased risk of myocardial infarction, stroke, renal damage, and blindness.1 Although at least10 genes have been shown to increase blood pressure, the pathogenesis of steroid hypertension has been shown to be primarily linked to mutations that result in ectopic production of the adrenal corticosterone, or aldosterone.2 Hypertension has also been shown to have proinflammatory actions, which increase the formation of hydrogen peroxide (H2O2) and superoxide (O2-) within tissue and blood.3 4 5 Furthermore, superoxide accumulation has been implicated in the activation of nuclear factor-
B (NF-B).
6 NF-B transcriptionally
regulates many cellular genes implicated in early immune, acute phase,
and inflammatory responses, including interleukin (IL)-1ß, tumor
necrosis factor-
, IL-2, IL-6, IL-8, inducible NO synthase (iNOS),
cyclooxygenase (COX)-2, intracellular adhesion
molecules, and many antioxidant
systems.7 Free radicals and
other reactive oxygen species (ROS) are generated by all aerobic cells
and have been shown to participate in many deleterious reactions, in
particular, reduced formation of endothelial NO
synthase (eNOS)8 9
and increased oxidative
stress.10
Endogenous NO plays an important role in the regulation of
blood pressure by maintaining vascular smooth muscle in a partially
relaxed state. During hypertension, the endogenous
vasodilatory effect of NO is prevented due to interaction with ROS,
specifically superoxide, thus resulting in increased vascular
resistance and elevation of blood
pressure.3 11 12
Antioxidant treatment has been shown to have beneficial
effects on NO metabolism and the pathogenesis observed in
angiotensin (Ang)
II13 – and
lead14 -induced hypertension.
In vivo and in vitro studies have shown that pyrrolidinedithiocarbamate
(PDTC) is a potent antioxidant and NF-B
antagonist.9 13 15
Furthermore, Ang II–receiving rats treated with PDTC exhibit decreased
systolic blood pressure and partial amelioration of end-organ
damage.13 In other studies,
the antioxidant Tempol (4-hydroxy-2,2,6,6-tetramethyl
piperidinoxyl) has been shown to normalize blood pressure in
spontaneously hypertensive rats
(SHR).16 Tempol is a
membrane-stable, membrane-permeable, metal-independent superoxide
dismutase (SOD) mimetic that has been shown to be specific for
superoxide.16 17 18
To date, ROS accumulation has been reported in deoxycorticosterone
acetate (DOCA)-salt
hypertension,3 SHR and
stroke-prone spontaneously hypertensive rats
(SHRSP),5 lead-induced
hypertension,13 and
essential hypertension.19
Previously, we reported that mineralocorticoid hypertensive rats
developed increased superoxide formation compounded with increased
renal monocyte/macrophage infiltration and NF-B
activation.20 We therefore
tested the hypothesis that prolonged antioxidant administration
inhibits superoxide accumulation, lowers systolic blood
pressure, and reduces NF-B activation in mineralocorticoid
hypertensive rats.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Silastic was from Dow Corning. DOCA, PMSF, dithiothreitol (DTT), Lucigenin, EDTA, and protease inhibitor cocktail were from Sigma Chemical Co. Pentobarbital was from The Butler Company. Ketamine and xylazine were from Fort Dodge Animal Health. Monocyte/macrophage ED-1 antibody was from Serotec. Tyramide signal amplification (TSA) kit was from NEN Life Science. Mouse HRP
and streptavidin-FITC were from Jackson ImmunoResearch.
DOCA-Salt Rats
Experiments were conducted on male Sprague-Dawley
rats treated with mineralocorticoid for 28 days. All procedures were
performed according to institutional guidelines. Male Sprague-Dawley
rats were anesthetized with an intramuscular injection of 100
mg/kg ketamine/20 mg/kg xylazine. A midscapular incision was
made, and a Silastic sheet containing DOCA (200 mg/kg body wt) was
inserted subcutaneously. A right flank incision was made, and a
uninephrectomy was performed. Rats treated with DOCA alone received 1%
NaCl and 0.1% KCl in drinking water, whereas 10 DOCA-treated rats
received drinking water with 1 mmol/L Tempol,1% NaCl, and 0.1%
KCl. Ten DOCA-treated rats also received PDTC (200 mg/kg body wt IP)
and were given drinking water that contained 1% NaCl and 0.1% KCl.
These concentrations of Tempol and PDTC have been shown to effectively
reduce oxidative stress and NF-B activation in intact
rats.13 16
Sham-operated rats underwent nephrectomy without the implantation of a
Silastic/DOCA pellet. Twenty-eight days after implantation, blood
pressure was measured with the tail cuff method (pneumatic transducer),
and the rats were anesthetized with a ketamine/xylazine
cocktail. The kidney and aorta was carefully removed, cleaned of excess
fat, and placed in PSS composed of (mmol/L) NaCl 130, KCl 4.7,
KH2PO4 1.18,
MgSO4-7H2O 1.17,
NaHCO3 14.9, dextrose 5.5, EDTA 0.26, and
CaCl2 1.6. The kidney was sectioned into 1- to
2-mm slices, and the aorta was cut into 2- to 3-mm
rings.
Lucigenin Assay
Lucigenin chemiluminescence was used to measure
superoxide production. Details of this assay have been
published
previously.21 22
In recent studies, 5 µmol/L lucigenin has been shown to correlate
well with electron spin resonance as a quantitative measure of
superoxide
production.23 24
After preparation, aortic sections were placed in PSS and allowed to
equilibrate for 30 minutes at 37°C. Scintillation vials that
contained 2 mL PSS buffer with 5 µmol/L lucigenin were placed into a
scintillation counter (Beckman LS 6000IC) and switched to
out-of-coincidence mode. After dark adaptation, background counts were
recorded and aortic rings were added to the vial. Scintillation
counts were recorded every minute for 20 minutes, and counts
between the 15- to 20-minute interval were averaged. Sections were
dried in an oven for 24 hours, and counts were expressed as counts
above background per milligram of dried tissue.
Immunohistochemistry
Frozen kidneys were cryosectioned at 7-µm thickness
and air dried as previously
described.13 Sections were
fixed with cold acetone, washed with PBS, blocked with blocking buffer
(3% calf serum, 0.1% Tween 20, 1x PBS), and incubated for 60 minutes
in a humid chamber at room temperature with primary monoclonal anti-rat
monocyte/macrophage ED-1 (1:250 in blocking buffer). After a
60-minute incubation, sections were washed with PBS and incubated with
bridging peroxidase-conjugated antibody (HRPMouse; 1:5000 in
blocking buffer) for 30 minutes. Sections were then washed, and TSA was
performed for 4 minutes according to a modification of the
manufacturer’s protocol. The tyramide was detected with
Streptavidin-FITC 1:100 through incubation for 1 hour followed by
washing. Immunoreactivity was visualized with a Ziess Axioplan 2
microscope, and photographs were taken with Zeiss Axiocam. Ten
different sections of each kidney (5 kidneys per group) were
analyzed. ED-1-abeled monocytes/macrophages from
anatomically equivalent sections of each kidney were counted by an
outside observer who was blinded as to treatment.
Electrophoretic Mobility Shift Assay
Tissue extractions and electrophoretic mobility
shift assay (EMSA) for the transcription factor NF-B were performed
as described
previously.25 26
Kidneys were frozen and divided into 0.2-g sections. Kidney sections
were pulverized in liquid nitrogen with a stainless steel mortar and
pestle and resuspended in 1.5 mL hypotonic buffer containing protease
inhibitor cocktail composed of (mmol/L) 10 mmol/L
HEPES-KOH, pH 7.9, 10 mmol/L KCl, 1.5 mmol/L
MgCl2, 0.5 mmol/L DTT, and protease
inhibitor cocktail in a glass homogenizer,
followed by incubation for 15 minutes on ice. The tissue was
homogenized with 10 strokes in the presence of 1% NP-40.
The suspension was centrifuged
(13 600g, 4 minutes, 4°C),
and the pellet was washed with 1 mL hypotonic buffer. The suspension
was recentrifuged
(13 600g, 4 minutes, 4°C),
and the pellet was resuspended in salt solution (20 mmol/L
HEPES-KOH, pH 7.9, 25% glycerol, 1.5 mmol/L
MgCl2, 400 mmol/L KCl, 2 mmol/L EDTA,
0.5 mmol/L DTT, 0.5 mmol/L PMSF, and protease
inhibitor cocktail). The salt suspension containing glass
beads was rotated on a tube rotator (Sepco Scientific Equipment) for 30
minutes and centrifuged
(20 000g, 30 minutes, 4°C).
The sample was immediately frozen in liquid nitrogen. Protein
concentration was quantified according to the Bradford method. For
EMSA, the NF-B oligonucleotide was derived from the
rat iNOS promoter (-972 to -949) containing the upstream
NF-B–binding site26 :
5'-TGCCAGGGGGATTTTCCCTCT-3' and
5'-GAGAGAGGG-AAAATCCCCCTGG-3'. Each oligomer was labeled
with [-32P]dCTP, and the 3 other
nonradiolabeled dNTPs by the Klenow fragment of DNA polymerase I. Renal
extract with the same amount of protein (10 to 20 µg) was incubated
with 300 000 cpm of 32P-labeled
oligonucleotide at 30°C for 30 minutes in the gel
shift binding buffer [12 mmol/L HEPES, 10% glycerol, 4
mmol/L Tris-HCl, 60 mmol/L KCl, 1 mmol/L EDTA, 1 mmol/L
DTT, 2 µg poly(dL/dC), and 2.5 µg BSA) in a final volume of 25
µl. Subsequently, the free and the
oligonucleotide-bound proteins were separated with
electrophoresis on a native 5.5% polyacrylamide gel in 0.5x
Tris borate-EDTA buffer. After electrophoresis, the gel was dried and
exposed to Hyperfilm MP. The intensity of the bands was
analyzed with a PhosphorImager (Molecular Dynamics).
Competition experiments were conducted by adding excess unlabeled
NF-B oligonucleotide to the binding reaction
mixture.
Statistical Analysis
Data are presented as mean±SEM.
Statistically significant differences among groups were tested by ANOVA
and the Tukey multiple range test or
t test as appropriate. A value
of P<0.05 was considered
statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Treatment with the antioxidants PDTC or Tempol reduced systolic blood pressure in DOCA rats (130±5 and 142±5 mm Hg versus 199±3 mm Hg, respectively; 24 DOCA, 12 DOCA/PDTC, and 7 DOCA/Tempol; P<0.05) (Figure 1A). However, the magnitude of the reduction in blood pressure did not reach that observed in sham rats (113±2 mm Hg, P<0.05; 13 sham) (Figure 1A). There was no significant difference in blood pressure between sham rats and sham rats treated with PDTC or Tempol (113±2 mm Hg versus 117±2 and 120±5 mm Hg; 15 sham, 5 sham/PDTC, and 5 sham/Tempol; P<0.05). DOCA rats exhibited increased renal hypertrophy compared with sham rats (0.0080±0.0002 versus 0.0051±0.0001, kidney weight/total body weight; 19 DOCA, 7 DOCA/Tempol, and 15 sham; P<0.05). PDTC or Tempol treatment partially, but significantly, decreased renal hypertrophy compared with untreated DOCA rats (0.0074±0.0002 and 0.0065±0.0004 versus 0.0080±0.0002, kidney weight/total body weight; 19 DOCA and 10 DOCA/PDTC; P<0.05) (Figure 1B).
|
P<0.05 vs DOCA.As a means of measuring oxidative stress within the 4 treatment groups, we measured aortic superoxide production with lucigenin chemiluminescence. DOCA rat aorta had markedly increased superoxide production compared with sham rats (7153 versus 783 versus 3055±559 cpm/mg, 14 and 12, respectively) (Figure 1C). Treatment of DOCA rats with PDTC or Tempol markedly decreased superoxide production compared with untreated DOCA rats (2498±251 and 2939±469 versus 7153±783, respectively; P<0.05) (Figure 1C). There was no significant difference in PDTC- or Tempol-treated rats compared with sham rats (2498±251 and 2939±469 versus 3055±559 cpm/mg; 8, 8, and13, respectively; P>0.05) (Figure 1C).
We further investigated monocyte and macrophage infiltration in renal tissue. Monocyte/macrophage infiltration was localized mainly in the renal tubules (Figure 2). DOCA rats exhibited increased monocyte/macrophage infiltration compared with sham rats (42±5 versus 10±2 per field viewed; 5 in all groups, respectively; P<0.05) (Figures 2A, 2B, and 2E). DOCA rats treated with PDTC or Tempol exhibited decreased monocyte/macrophage infiltration compared with untreated DOCA rats (16±3 and 26±4 versus 42±5; respectively, P<0.05) (Figures 2B and 2C through 2E), but the amount of infiltration was higher than for sham rats (Figures 2A and 2C through 2E). There was no significant difference in monocyte/macrophage infiltration in sham/Tempol or sham/PDTC rats compared with untreated sham rats (results not shown).
|
Using EMSAs, we identified an increase in NF-B–binding
activity in renal tissue from DOCA rats compared with sham rats
(Figures 3A and 3C). Treatment with PDTC or Tempol resulted in
decreased NF-B–binding activity compared with untreated DOCA rats
(Figures 3A through 3C). Treatment with PDTC also resulted in
a significant decrease in NF-B–binding activity compared with sham
rats (0.81±0.12- versus 1.0-fold)
(Figures 3A and 3B). There was no significant difference in
binding activity between DOCA/Tempol–treated animals and sham animals
(Figure 3B). As control, DOCA-salt hypertensive rat renal
extracts were incubated with antibodies against NF-B subunits
anti-p50 and anti-p65. Supershift assay confirmed p65 and p50 binding
activity
(Figure 3C).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Several recent studies3 11 14 have provided convincing evidence that hypertension causes increased ROS accumulation. Other studies have also shown that ROS cause activation of NF-
B.6 9 NF-B
plays a critical role in the activation of multiple genes that
contribute to the inflammatory response and end-organ
damage.13 Here, we report
increased NF-B activation as well as increased ROS accumulation in
the mineralocorticoid hypertensive rat. We tested the hypothesis that
prolonged antioxidant administration inhibits superoxide accumulation,
lowers blood pressure, and reduces NF-B activation in
mineralocorticoid hypertensive rats. We found that antioxidants lower
blood pressure, normalize
O2-
production, reduce NF-B activation, and reduce
monocyte/macrophage infiltration. Furthermore, although we
found that antioxidants reduce NF-B activation and normalize
O2-
production, they only partially correct the elevated
systolic blood pressure and monocyte/macrophage
infiltration. Thus, it is likely that other mechanisms, not yet fully
identified, are participating in the hemodynamics and
renal disturbances.
Previous studies have been shown that Ang II-induced
hypertension cause renal hypertrophy, NF-B activation,
adhesion molecule upregulation, and monocyte/macrophage
infiltration.14 Our findings
in this low-renin model of hypertension suggests that NF-B
activation and monocyte/macrophage infiltration may be due to
locally produced cellular changes that result in ROS formation.
Previously, it has been shown that Ang II, thrombin,
platelet-derived growth factor, tumor necrosis factor-, and
lactosylceramide increase NAD(P)H oxidase activity, thus resulting in
superoxide
accumulation.27 28 29
Moreover, local cellular changes observed in mineralocorticoid
hypertension could also be manifested through the stimulation of
NAD(P)H oxidase. Therefore, further studies to better understand the
mechanism by which superoxide is generated in the mineralocorticoid
hypertensive rat are necessary.
Both superoxide and NO are highly reactive unstable free radicals that react together very rapidly to form peroxynitrate.26 This reaction occurs 3 times faster than the dismutation of superoxide by SOD, thus implying that superoxide generation in vascular tissue may inhibit the physiological function of NO.26 Also, it has been shown that experimental elevation of blood pressure and essential hypertension cause increased superoxide formation and decreased endothelium-dependent relaxation.11 19 Therefore, increased vascular O2- production observed in the aorta of the mineralocorticoid hypertensive rats may result in alteration in vascular endothelium-dependent relaxation due to decreased NO bioavailability.
Salt retention is characteristic of human hypertension and
can be achieved rapidly in the mineralocorticoid hypertensive rat
model. We chose to use the mineralocorticoid hypertensive rat model
because it shows a markedly depressed renin-angiotensin
system and because circulating Ang II has previously been shown to
increase monocyte/macrophage infiltration and vasculopathy in
the kidney and elsewhere.13
In other studies, it has also been shown that increased vascular
resistance due to arterial hypertension in humans results
in increased intrarenal vascular resistance, which causes renal
ischemia leading to renal
damage.30 31 The
present study shows that long-term hypertension in the presence of
low renin can cause induction in the renal inflammatory response,
resulting from ROS accumulation and NF-B activation. To examine the
pathogenesis caused by ROS accumulation, we used 2 potent antioxidants:
PDTC and Tempol. From the results obtained in this study, PDTC appears
to be a more potent antioxidant than Tempol, and the ability of PDTC to
cause complete inhibition of the inflammatory response may be due to
more than just its antioxidant effect. Therefore, further studies are
necessary to discern some of these effects.
In conclusion, our results indicate that prolonged
antioxidant administration normalizes superoxide accumulation, lowers
systolic blood pressure, and reduces NF-B activation in
mineralocorticoid hypertensive rats. Also, our results suggest that
many of the renal changes that occur during hypertension may be due in
part to the induction of signal transduction precursors that initiate
the inflammatory response. Therefore, further studies to identify the
pathophysiological implication of these precursors
on the hypertensive state are
necessary.
|
Acknowledgments |
|---|
This work was funded by grants from the National Institutes of Health (HL-18575 and HL-52958), a Systems and Integrative Physiology Training Grant (2-T32-GME0322-11), and a University of Michigan Rackham Merit Fellowship. Dr Richard Beswick is a current graduate student at the University of Michigan Department of Physiology. Dr Zhang is supported by a grant from the American Lung Association (RG-105-N). We would like to thank the laboratory personnel of David Harrison for their help with the lucigenin studies and Angeline Meadows for all of her technical support.
Received November 25, 2000; first decision November 30, 2000; accepted December 14, 2000.
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J. M. Moreno, I. Rodriguez Gomez, R. Wangensteen, M. Alvarez-Guerra, J. d. D. Luna, J. Garcia-Estan, and F. Vargas Tempol improves renal hemodynamics and pressure natriuresis in hyperthyroid rats Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2008; 294(3): R867 - R873. [Abstract] [Full Text] [PDF]
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A. A. Elmarakby, J. E. Quigley, J. D. Imig, J. S. Pollock, and D. M. Pollock TNF-{alpha} inhibition reduces renal injury in DOCA-salt hypertensive rats Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2008; 294(1): R76 - R83. [Abstract] [Full Text] [PDF]
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N. Tian, R. S. Moore, S. Braddy, R. A. Rose, J.-W. Gu, M. D. Hughson, and R. D. Manning Jr. Interactions between oxidative stress and inflammation in salt-sensitive hypertension Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3388 - H3395. [Abstract] [Full Text] [PDF]
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L. Yu, H.-F. Bao, J. L. Self, D. C. Eaton, and M. N. Helms Aldosterone-induced increases in superoxide production counters nitric oxide inhibition of epithelial Na channel activity in A6 distal nephron cells Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1666 - F1677. [Abstract] [Full Text] [PDF]
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 E. C. Chan, S. R. Datla, R. Dilley, H. Hickey, G. R. Drummond, and G. J. Dusting Adventitial application of the NADPH oxidase inhibitor apocynin in vivo reduces neointima formation and endothelial dysfunction in rabbits Cardiovasc Res, September 1, 2007; 75(4): 710 - 718. [Abstract] [Full Text] [PDF]
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Y. Bravo, Y. Quiroz, A. Ferrebuz, N. D. Vaziri, and B. Rodriguez-Iturbe Mycophenolate mofetil administration reduces renal inflammation, oxidative stress, and arterial pressure in rats with lead-induced hypertension Am J Physiol Renal Physiol, August 1, 2007; 293(2): F616 - F623. [Abstract] [Full Text] [PDF]
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K. A. Nath, L. V. d'Uscio, J. P. Juncos, A. J. Croatt, M. C. Manriquez, S. T. Pittock, and Z. S. Katusic An analysis of the DOCA-salt model of hypertension in HO-1-/- mice and the Gunn rat Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H333 - H342. [Abstract] [Full Text] [PDF]
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 Y. Hirono, T. Yoshimoto, N. Suzuki, T. Sugiyama, M. Sakurada, S. Takai, N. Kobayashi, M. Shichiri, and Y. Hirata Angiotensin II Receptor Type 1-Mediated Vascular Oxidative Stress and Proinflammatory Gene Expression in Aldosterone-Induced Hypertension: The Possible Role of Local Renin-Angiotensin System Endocrinology, April 1, 2007; 148(4): 1688 - 1696. [Abstract] [Full Text] [PDF]
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 A. A. Banday, A. B. Muhammad, F. R. Fazili, and M. Lokhandwala Mechanisms of Oxidative Stress-Induced Increase in Salt Sensitivity and Development of Hypertension in Sprague-Dawley Rats Hypertension, March 1, 2007; 49(3): 664 - 671. [Abstract] [Full Text] [PDF]
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M. R. Hayden, N. A. Chowdhury, S. A. Cooper, A. Whaley-Connell, J. Habibi, L. Witte, C. Wiedmeyer, C. M. Manrique, G. Lastra, C. Ferrario, et al. Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat Am J Physiol Renal Physiol, February 1, 2007; 292(2): F861 - F867. [Abstract] [Full Text] [PDF]
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 P. Pacher, J. S. Beckman, and L. Liaudet Nitric Oxide and Peroxynitrite in Health and Disease Physiol Rev, January 1, 2007; 87(1): 315 - 424. [Abstract] [Full Text] [PDF]
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J.-W. Gu, N. Tian, M. Shparago, W. Tan, A. P. Bailey, and R. D. Manning Jr. Renal NF-{kappa}B activation and TNF-{alpha} upregulation correlate with salt-sensitive hypertension in Dahl salt-sensitive rats Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2006; 291(6): R1817 - R1824. [Abstract] [Full Text] [PDF]
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H. Xu, W. F. Jackson, G. D. Fink, and J. J. Galligan Activation of Potassium Channels by Tempol in Arterial Smooth Muscle Cells From Normotensive and Deoxycorticosterone Acetate-Salt Hypertensive Rats Hypertension, December 1, 2006; 48(6): 1080 - 1087. [Abstract] [Full Text] [PDF]
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T. M. Paravicini and R. M. Touyz Redox signaling in hypertension Cardiovasc Res, July 15, 2006; 71(2): 247 - 258. [Abstract] [Full Text] [PDF]
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 J. C. Sullivan, J. S. Pollock, and D. M. Pollock Superoxide-dependent hypertension in male and female endothelin B receptor-deficient rats. Experimental Biology and Medicine, June 1, 2006; 231(6): 818 - 823. [Abstract] [Full Text] [PDF]
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C. L. Laffer, R. J. Bolterman, J. C. Romero, and F. Elijovich Effect of Salt on Isoprostanes in Salt-Sensitive Essential Hypertension Hypertension, March 1, 2006; 47(3): 434 - 440. [Abstract] [Full Text] [PDF]
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 F. Vargas, J. M. Moreno, I. Rodriguez-Gomez, R. Wangensteen, A. Osuna, M. Alvarez-Guerra, and J. Garcia-Estan Vascular and renal function in experimental thyroid disorders Eur. J. Endocrinol., February 1, 2006; 154(2): 197 - 212. [Abstract] [Full Text] [PDF]
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A. Vidal, Y. Sun, S. K. Bhattacharya, R. A. Ahokas, I. C. Gerling, and K. T. Weber Calcium paradox of aldosteronism and the role of the parathyroid glands Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H286 - H294. [Abstract] [Full Text] [PDF]
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H. Xu, X. Bian, S. W. Watts, and A. Hlavacova Activation of Vascular BK Channel by Tempol in DOCA-Salt Hypertensive Rats Hypertension, November 1, 2005; 46(5): 1154 - 1162. [Abstract] [Full Text] [PDF]
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 A. Dikalova, R. Clempus, B. Lassegue, G. Cheng, J. McCoy, S. Dikalov, A. S. Martin, A. Lyle, D. S. Weber, D. Weiss, et al. Nox1 Overexpression Potentiates Angiotensin II-Induced Hypertension and Vascular Smooth Muscle Hypertrophy in Transgenic Mice Circulation, October 25, 2005; 112(17): 2668 - 2676. [Abstract] [Full Text] [PDF]
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D. M. Pollock Endothelin, Angiotensin, and Oxidative Stress in Hypertension Hypertension, April 1, 2005; 45(4): 477 - 480. [Full Text] [PDF]
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A. A. Elmarakby, E. D. Loomis, J. S. Pollock, and D. M. Pollock NADPH Oxidase Inhibition Attenuates Oxidative Stress but Not Hypertension Produced by Chronic ET-1 Hypertension, February 1, 2005; 45(2): 283 - 287. [Abstract] [Full Text] [PDF]
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W. J. Welch, J. Blau, H. Xie, T. Chabrashvili, and C. S. Wilcox Angiotensin-induced defects in renal oxygenation: role of oxidative stress Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H22 - H28. [Abstract] [Full Text] [PDF]
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S. C. Supowit, A. Rao, M. C. Bowers, H. Zhao, G. Fink, B. Steficek, P. Patel, K. A. Katki, and D. J. DiPette Calcitonin Gene-Related Peptide Protects Against Hypertension-Induced Heart and Kidney Damage Hypertension, January 1, 2005; 45(1): 109 - 114. [Abstract] [Full Text] [PDF]
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J. M. Williams, J. S. Pollock, and D. M. Pollock Arterial Pressure Response to the Antioxidant Tempol and ETB Receptor Blockade in Rats on a High-Salt Diet Hypertension, November 1, 2004; 44(5): 770 - 775. [Abstract] [Full Text] [PDF]
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V. M. Campese, S. Ye, H. Zhong, V. Yanamadala, Z. Ye, and J. Chiu Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H695 - H703. [Abstract] [Full Text] [PDF]
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 L. Wu, M. H. Noyan Ashraf, M. Facci, R. Wang, P. G. Paterson, A. Ferrie, and B. H. J. Juurlink Dietary approach to attenuate oxidative stress, hypertension, and inflammation in the cardiovascular system PNAS, May 4, 2004; 101(18): 7094 - 7099. [Abstract] [Full Text] [PDF]
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B. Rodriguez-Iturbe, N. D. Vaziri, J. Herrera-Acosta, and R. J. Johnson Oxidative stress, renal infiltration of immune cells, and salt-sensitive hypertension: all for one and one for all Am J Physiol Renal Physiol, April 1, 2004; 286(4): F606 - F616. [Abstract] [Full Text] [PDF]
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A. Nishiyama, L. Yao, Y. Nagai, K. Miyata, M. Yoshizumi, S. Kagami, S. Kondo, H. Kiyomoto, T. Shokoji, S. Kimura, et al. Possible Contributions of Reactive Oxygen Species and Mitogen-Activated Protein Kinase to Renal Injury in Aldosterone/Salt-Induced Hypertensive Rats Hypertension, April 1, 2004; 43(4): 841 - 848. [Abstract] [Full Text] [PDF]
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K. T. Weber From Inflammation to Fibrosis: A Stiff Stretch of Highway Hypertension, April 1, 2004; 43(4): 716 - 719. [Full Text] [PDF]
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G. E. Callera, A. C. Montezano, R. M. Touyz, T. M.T. Zorn, M. H. C. Carvalho, Z. B. Fortes, D. Nigro, E. L. Schiffrin, and R. C. Tostes ETA Receptor Mediates Altered Leukocyte-Endothelial Cell Interaction and Adhesion Molecules Expression in DOCA-Salt Rats Hypertension, April 1, 2004; 43(4): 872 - 879. [Abstract] [Full Text] [PDF]
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S. H. Mehta, R. C. Webb, A. Ergul, A. Tawak, and A. M. Dorrance Neuroprotection by tempol in a model of iron-induced oxidative stress in acute ischemic stroke Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2004; 286(2): R283 - R288. [Abstract] [Full Text] [PDF]
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H. Xu, G. D. Fink, and J. J. Galligan Tempol Lowers Blood Pressure and Sympathetic Nerve Activity But Not Vascular O2- in DOCA-Salt Rats Hypertension, February 1, 2004; 43(2): 329 - 334. [Abstract] [Full Text] [PDF]
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Y. Taniyama and K. K. Griendling Reactive Oxygen Species in the Vasculature: Molecular and Cellular Mechanisms Hypertension, December 1, 2003; 42(6): 1075 - 1081. [Abstract] [Full Text] [PDF]
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G. E. Callera, R. M. Touyz, S. A. Teixeira, M. N. Muscara, M. H. C. Carvalho, Z. B. Fortes, D. Nigro, E. L. Schiffrin, and R. C. Tostes ETA Receptor Blockade Decreases Vascular Superoxide Generation in DOCA-Salt Hypertension Hypertension, October 1, 2003; 42(4): 811 - 817. [Abstract] [Full Text] [PDF]
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B. Lassegue and R. E. Clempus Vascular NAD(P)H oxidases: specific features, expression, and regulation Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R277 - R297. [Abstract] [Full Text] [PDF]
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A. Makino, M. M. Skelton, A.-P. Zou, and A. W. Cowley Jr Increased Renal Medullary H2O2 Leads to Hypertension Hypertension, July 1, 2003; 42(1): 25 - 30. [Abstract] [Full Text] [PDF]
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J. F. Reckelhoff and J. C. Romero Role of oxidative stress in angiotensin-induced hypertension Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2003; 284(4): R893 - R912. [Abstract] [Full Text] [PDF]
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K. M. Hoagland, K. G. Maier, and R. J. Roman Contributions of 20-HETE to the Antihypertensive Effects of Tempol in Dahl Salt-Sensitive Rats Hypertension, March 1, 2003; 41(3): 697 - 702. [Abstract] [Full Text] [PDF]
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T. Shokoji, A. Nishiyama, Y. Fujisawa, H. Hitomi, H. Kiyomoto, N. Takahashi, S. Kimura, M. Kohno, and Y. Abe Renal Sympathetic Nerve Responses to Tempol in Spontaneously Hypertensive Rats Hypertension, February 1, 2003; 41(2): 266 - 273. [Abstract] [Full Text] [PDF]
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D. N. Muller, A. Mullally, R. Dechend, J.-K. Park, A. Fiebeler, B. Pilz, B.-M. Loffler, D. Blum-Kaelin, S. Masur, H. Dehmlow, et al. Endothelin-Converting Enzyme Inhibition Ameliorates Angiotensin II-Induced Cardiac Damage Hypertension, December 1, 2002; 40(6): 840 - 846. [Abstract] [Full Text] [PDF]
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 Y. Sun, J. Zhang, L. Lu, S. S. Chen, M. T. Quinn, and K. T. Weber Aldosterone-Induced Inflammation in the Rat Heart : Role of Oxidative Stress Am. J. Pathol., November 1, 2002; 161(5): 1773 - 1781. [Abstract] [Full Text] [PDF]
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H. Xu, G. D. Fink, and J. J. Galligan Nitric oxide-independent effects of tempol on sympathetic nerve activity and blood pressure in DOCA-salt rats Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H885 - H892. [Abstract] [Full Text] [PDF]
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L. Wu and B. H.J. Juurlink Increased Methylglyoxal and Oxidative Stress in Hypertensive Rat Vascular Smooth Muscle Cells Hypertension, March 1, 2002; 39(3): 809 - 814. [Abstract] [Full Text] [PDF]
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C. G. Schnackenberg Physiological and pathophysiological roles of oxygen radicals in the renal microvasculature Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2002; 282(2): R335 - R342. [Abstract] [Full Text] [PDF]
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A. Makino, M. M. Skelton, A.-P. Zou, R. J. Roman, and A. W. Cowley Jr Increased Renal Medullary Oxidative Stress Produces Hypertension Hypertension, February 1, 2002; 39(2): 667 - 672. [Abstract] [Full Text] [PDF]
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F. Z. Ammarguellat, P. O. Gannon, F. Amiri, and E. L. Schiffrin Fibrosis, Matrix Metalloproteinases, and Inflammation in the Heart of DOCA-Salt Hypertensive Rats: Role of ETA Receptors Hypertension, February 1, 2002; 39(2): 679 - 684. [Abstract] [Full Text] [PDF]
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R. A. Beswick, A. M. Dorrance, R. Leite, and R. C. Webb NADH/NADPH Oxidase and Enhanced Superoxide Production in the Mineralocorticoid Hypertensive Rat Hypertension, November 1, 2001; 38(5): 1107 - 1111. [Abstract] [Full Text] [PDF]
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H. Xu, G. D. Fink, A. Chen, S. Watts, and J. J. Galligan Nitric oxide-independent effects of tempol on sympathetic nerve activity and blood pressure in normotensive rats Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H975 - H980. [Abstract] [Full Text] [PDF]
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