(Hypertension. 2000;36:957.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Effect of Antioxidant Therapy on Blood Pressure and NO Synthase Expression in Hypertensive Rats
From the Division of Nephrology, Department of Medicine, University of California, Irvine.
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Abstract |
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Abstract—Earlier studies have demonstrated evidence for increased reactive oxygen species, enhanced NO synthase (NOS) expression, and elevated NO production in spontaneously hypertensive rats (SHR). Given the negative-feedback regulation of NOS by NO, we hypothesized that enhanced NO inactivation by ROS may contribute to compensatory upregulation of NOS in SHR. The present study was designed to test this hypothesis. Eight-week-old male SHR and Wistar-Kyoto rats were treated for 3 weeks with either a placebo or the potent antioxidant, lazaroid (desmethyltirilazad, 10 mg · kg-1 · d-1, by gastric gavage). Tail arterial blood pressure, urinary excretion of NO metabolites (ie, nitrate and nitrite), and immunodetectable NOS isotype proteins in the vascular, renal, cardiac, and cerebral tissues were measured. The placebo-treated SHR group showed a marked elevation of blood pressure and a significant upregulation of aorta, kidney, and cardiac tissue endothelial and inducible NOS (eNOS and iNOS, respectively) proteins and of brain and renal tissue neuronal NOS. Lazaroid therapy ameliorated hypertension and mitigated the upregulation of eNOS and iNOS in vascular, renal, and cardiac tissues but had limited effect on the expression of renal and brain neuronal NOS. In contrast, lazaroid therapy had no effect on blood pressure, urinary nitrate and nitrite excretion, or tissue NOS isotype expressions in the Wistar-Kyoto group. These findings support the role of oxidative stress in the genesis and/or maintenance of hypertension and compensatory upregulation of the expression of eNOS and iNOS in SHR.
Key Words: stress • free radicals • hypertension, experimental • antioxidants • nitric oxide • nitric oxide synthase
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Introduction |
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We have recently demonstrated a marked upregulation of renal and vascular expressions of endothelial and inducible NO synthase (eNOS and iNOS, respectively) proteins in young spontaneously hypertensive rats (SHR).1 These observations substantiated the results of several earlier studies,2 3 4 5 6 7 which provided evidence for enhanced NO systems in young and adult SHR. The presence of severe hypertension in the face of a marked increase in the NO system may be indicative of enhanced NO inactivation. Superoxide and other reactive oxygen species (ROS) can avidly react with and inactivate NO.8 9 10 11 It is of note that several recent studies have provided compelling evidence for increased ROS activity in SHR.12 13 14 15 Therefore, the associated increased ROS activity can enhance NO inactivation and reduce bioactive NO. This can, in turn, contribute to the maintenance of hypertension and cause a compensatory upregulation of NO synthase (NOS) isotype expression. In fact, administration of the cell-permeable superoxide dismutase mimetic, tempol, has been recently shown to lower blood pressure and increase NO availability in SHR.14 We have recently shown that biologically active NO exerts a negative-feedback influence on NOS expression in cultured human endothelial cells.16 Thus, increased ROS-mediated inactivation of NO can potentially contribute to a compensatory upregulation of NOS via a reduction in NO bioavailability, as recently shown in lead-induced hypertension.11 17 The present study was undertaken to test the hypothesis that antioxidant therapy may alleviate hypertension and reverse the compensatory upregulation of NOS isotypes in SHR.
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Methods |
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Animals
Eight-week-old male SHR (Harlan Sprague Dawley Inc, Indianapolis, Ind) were housed in a temperature-controlled light-regulated space with 12-hour light and dark cycles. The animals were allowed free access to a low nitrate basic rat chow and water. The animals were randomly assigned to the lazaroid-treated and vehicle-treated control groups. The lazaroid-treated group received a potent antioxidant lazaroid compound, desmethyltirilazad (U7489G, UpJohn Inc), at 10 mg · kg-1 · d-1 by gastric gavage for 3 weeks. The placebo-treated SHR group received the inactive vehicle instead. A control group of age-matched male genetically normotensive Wistar-Kyoto rats (WKY) served as controls. To determine the possible effect of lazaroid therapy in genetically normotensive animals, the studies were repeated comparing 2 groups of WKY treated with lazaroid and placebo, as described for the SHR group. A minimum of 6 animals was included in each group. Timed urine collections were obtained by placing the rats in metabolic cages. Food was withdrawn, but water was provided the night before and during the collection period.
At the conclusion of the 3-week treatment period, the animals were anesthetized with intraperitoneal injections of pentobarbital sodium (Nembutal, 50 mg/kg). Blood was obtained by cardiac puncture, and brain, heart (left ventricle), thoracic aorta, and kidneys were immediately harvested, cleaned, and promptly frozen in liquid nitrogen. The samples were then stored at -70°C until they were processed.
Measurement of Arterial Pressure
Arterial pressure was measured by tail
plethysmography as described in our earlier studies.18
Briefly conscious rats were placed on a heated pad in a
temperature-controlled quiet space. They were allowed to rest for 15
minutes with the tail placed inside a tail cuff. The cuff was inflated
and released several times to condition the animal to the procedure.
Thereafter, 4 consecutive measurements were taken by a rat-tail blood
pressure monitor, recorded by a student oscillograph (Harvard
Apparatus Inc), and averaged for presentation.
Measurement of Total NOx
Urine nitrate and nitrite (NOx)
concentration was measured by using the purge system of a model 270B
nitric oxide analyzer (NOA228, Sievers Instruments Inc) in a
manner that was identical to that described in our earlier
studies.19
Tissue Preparation and Western Blot Analyses
Kidney, aorta, heart, and brain tissues were prepared for
measurements of endothelial NOS (eNOS), inducible NOS
(iNOS), and neuronal NOS (nNOS) protein abundance by Western blot
analysis. The procedures were performed in a manner that was
identical to that described in our previous studies using anti-eNOS,
anti-iNOS, and anti-nNOS antibodies (Transduction
Laboratories).20 21 Briefly, aorta, heart, brain, and
kidney tissue protein preparations (50 µg for the aorta, heart, and
brain; 100 µg for the kidney) were size-fractionated on 4% to 12%
Tris-glycine gel (Novex) at 120 V for 3 hours. In preliminary
experiments, we found that the given protein concentrations were within
the linear range of detection for our Western blot technique. After
electrophoresis, proteins were transferred onto Hybond-ECL membranes
(Amersham Life Science Inc) at 400 mA for 120 minutes with the use of
the Novex transfer system. The membrane was prehybridized in 10 mL
buffer A (10 mmol/L Tris hydrochloride, pH 7.5, 100 mmol/L
NaCl, 0.1% Tween 20, and 10% nonfat milk powder) for 1 hour and then
hybridized for an additional 1-hour period in the same buffer
containing 10 µL of the given anti-NOS monoclonal antibody (1:1000).
The membrane was then washed for 30 minutes in a shaking bath, with the
wash buffer (buffer A without nonfat milk) changed every 5 minutes
before 1 hour of incubation in buffer A plus goat anti-mouse
IgG-horseradish peroxidase at a final titer of 1:1000. Experiments were
performed at room temperature. The washes were repeated before the
membrane was developed with a light-emitting nonradioactive method
using ECL reagent (Amersham Inc). The membrane was then subjected to
autoluminography for 1 to 5 minutes. The autoluminographs were
scanned with a laser densitometer (model PD1211, Molecular Dynamics) to
determine the relative optical densities of the bands. In all
instances, the membranes were stained with Ponceau stain before
prehybridization. This step verified the uniformity of protein load and
transfer efficiency across the test samples.
In an attempt to explore possible cross-reactivity between eNOS and iNOS in the vascular tissue, we probed cultured endothelial cell protein preparations for immunodetectable iNOS by Western blot. No detectable iNOS was found, whereas abundant eNOS was present in this preparation. This observation excludes discernible cross-reactivity with the antibodies used in this system. In addition, the experiments suggested that constitutively expressed iNOS in the vascular tissue is most likely contained in cells other than the endothelial lining.
To discern the approximate comparison of eNOS and iNOS protein
abundance in the vascular, renal, and cardiac tissues, we carried a set
of separate experiments in which simultaneous Western blots
were obtained under identical conditions for both NOS isotypes. On
every occasion, the optical densities of the iNOS bands were 
200%
less than those of the corresponding eNOS bands. These findings suggest
that constitutively expressed iNOS protein abundance is substantially
less than that of eNOS. However, given the uncertainty regarding the
antigen binding potency of the 2 antibodies, accurate assessment of
relative quantities of the 2 enzymes is not possible by the methods
used in the present study.
Data Analysis
ANOVA was used in statistical analysis of the data,
which are presented as mean±SEM. A value of P<0.05
was considered significant.
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Results |
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Blood Pressure and NOx Excretion
As expected, the placebo-treated SHR group exhibited a marked elevation in arterial blood pressure compared with the WKY control group. Antioxidant therapy with the lazaroid compound resulted in a significant amelioration of hypertension. In confirmation of our earlier study,1 compared with the WKY control group, the placebo-treated SHR group showed a significant increase in urinary excretion of NOx. Antioxidant therapy lowered the urinary NOx excretion in the lazaroid-treated SHR group toward values seen in the control animals. In contrast to the data obtained in the SHR group, lazaroid therapy had no effect on either blood pressure or urinary NOx excretion in the WKY group (Figure 1).
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Aorta NOS Isotypes
Compared with the WKY group, the placebo-treated SHR group showed
a marked upregulation of eNOS and iNOS protein abundance in the aorta.
Antioxidant therapy resulted in a significant attenuation of aorta eNOS
and iNOS protein expressions in the lazaroid-treated SHR group (Figure 2). However, lazaroid therapy had no
effect on either eNOS or iNOS expression in WKY aortas (Figure 3).
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Kidney NOS Isotypes
Kidney tissue eNOS and iNOS protein abundance was markedly
increased in the placebo-treated SHR group relative to the
corresponding values found in the WKY control group. The upregulations
of the kidney tissue eNOS and iNOS protein expressions were
significantly attenuated by antioxidant therapy in the lazaroid-treated
SHR group. As with eNOS and iNOS proteins, renal tissue nNOS protein
abundance was significantly increased in the placebo-treated SHR group.
However, the magnitude of the lazaroid-induced fall in renal nNOS
protein expression was far less than that seen with eNOS and iNOS
proteins (Figure 4). In contrast to data
obtained in the SHR group, lazaroid therapy had no effect on either
eNOS, iNOS, or nNOS in the kidneys of the WKY group (Figures 3).
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Brain nNOS Protein
Compared with the WKY control group, the placebo-treated SHR group
showed a marked increase in brain tissue nNOS protein abundance.
Lazaroid therapy caused a minimal reduction in immunodetectable nNOS
protein abundance in the SHR brain and no effect in the WKY brain
(Figures 3 and 5).
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Heart NOS Isotypes
The placebo-treated SHR exhibited a marked upregulation of cardiac
eNOS and iNOS protein expressions. Antioxidant therapy caused a
significant but partial reversal of the cardiac eNOS and iNOS protein
elevations in the lazaroid-treated SHR. However, lazaroid therapy had
no effect on cardiac tissue NOS isotype expressions in WKY (Figures 3 and 6).
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Discussion |
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Several recent studies have provided compelling evidence for increased ROS generation in the vascular tissues of SHR.13 22 23 24 For instance, using fluorescence microscopy, Suzuki et al23 have demonstrated enhanced superoxide production in mesenteric arterioles of SHR in vivo. Likewise Grunfeld et al24 have reported increased superoxide generation in cultured aortic endothelial cells from SHR compared with corresponding cells from WKY. Moreover, Cosentino et al13 have shown increased superoxide and hydrogen peroxide release in aortic strips prepared from SHR. ROS are thought to contribute to the generation and/or maintenance of hypertension in SHR by several mechanisms. These include inactivation of endothelium-derived NO,12 14 nonenzymatic generation of vasoconstrictive F2-isoprostanes from arachidonic acid peroxidation,15 and depletion of the NOS cofactor tetrahydrobiopterin.13 The role of oxidative stress in the genesis and maintenance of hypertension in SHR is supported by amelioration of hypertension with antioxidant administration.14 15 22 23 25 26
In addition to SHR, oxidative stress has been implicated in a variety of other hypertensive disorders, including lead-induced hypertension,11 18 27 28 uremic hypertension,19 cyclosporine-induced hypertension,29 30 salt-sensitive hypertension,31 32 preeclampsia,33 essential hypertension,34 35 36 37 and diabetes.38 39 In addition, long-term consumption of high-fat and highly refined sugar diets, which are known to cause oxidative stress,40 41 has been shown to produce hypertension in normotensive animals.42 43 Finally, we have recently shown that induction of oxidative stress by glutathione depletion leads to severe sustained hypertension and depressed NO availability in genetically normotensive Sprague-Dawley rats.44 Thus, oxidative stress appears to be a common feature of hypertensive disorders of diverse origins.
ROS avidly react with and inactivate NO.8 9 10 ROS-mediated NO inactivation can contribute to hypertension and endothelial dysfunction by limiting the availability of biologically active NO. Earlier studies have revealed that NO can rapidly inhibit NOS enzymatic activity, presumably by interacting with the iron core of the heme moiety of the enzyme.45 In addition, we have recently shown that NO exerts a negative-feedback role in the regulation of endothelial NOS expression.16 On the basis of these considerations, we hypothesized that upregulation of renal and vascular NOS isotypes found in our earlier study of SHR1 may be due to the ROS-mediated reduction of NO availability and, hence, diminished negative-feedback regulation of NOS expression. If true, amelioration of oxidative stress by antioxidant therapy should mitigate the upregulation of NOS isotypes in SHR.
In the present study, the untreated SHR group exhibited a significant elevation of arterial blood pressure, increased urinary NO metabolite excretion, and marked upregulation of renal, vascular, and cardiac eNOS and iNOS and of brain and kidney nNOS protein expressions. Administration of the potent antioxidant, desmethyltirilazad, for 3 weeks resulted in a significant amelioration of hypertension despite marked reductions in urinary NOx excretion and renal, vascular, and cardiac NOS isotype expressions. These data suggest that alleviation of oxidative stress by antioxidant therapy diminishes ROS-mediated NO inactivation and, thereby, raises the availability of bioactive NO in the treated SHR. The rise in the bioactive NO availability, in turn, enhances NO-mediated vasodilatory tone, which could, in part, account for the observed amelioration of hypertension. In addition, improved NO availability restores the NO-mediated negative-feedback regulation of NOS activity45 and protein expression16 and, thereby, reverses the compensatory upregulation of NOS isotypes in the treated SHR. The observed effects of antioxidant therapy on blood pressure and NO metabolism in SHR were not due to a nonspecific action of the drug used. The latter assertion is substantiated by the lack of any effect of lazaroid therapy on blood pressure, urinary NOx excretion, or tissue NOS isotype expressions in the normotensive WKY. The latter findings parallel those of our recent studies demonstrating that in the absence of oxidative stress, antioxidant therapy has no effect on blood pressure, urinary NOx excretion, or NOS expression.11 17 The results of the present study in SHR are consistent with those of our recent studies in rats with lead-induced hypertension, which is marked by oxidative stress and compensatory upregulation of renal and vascular NOS isotypes.11 17 18 Administration of desmethyltirilazad in animals with lead-induced hypertension reversed oxidative stress, improved NO availability, and ameliorated hypertension27 in a manner similar to that found in SHR in the present study. In a more recent series of studies, we found that amelioration of oxidative stress and hypertension with a vitamin E–fortified diet was coupled with enhanced NO availability and a reversal of compensatory upregulation of renal and vascular NOS isotype expressions in rats with lead-induced hypertension,11 17 mirroring the findings of the present study in SHR.
The untreated SHR exhibited a marked increase in urinary total NOx excretion despite avid ROS-mediated oxidation and sequestration of NO as peroxynitrite (ONOO-) and nitrated tyrosine and other molecules. These events are expected to lower rather than raise urinary NOx excretion. Although this is true for the unsteady-state phase, isomerization of ONOO- and turnover of the nitrated molecules will eventually lead to formation of NO3- and NO2-, which are excreted in the urine. Thus, during a steady-state condition, such as chronic hypertension, urinary NOx reflects NO production despite ongoing ROS-mediated inactivation of NO.
The antioxidant used in the present study was desmethyltirilazad, which is a powerful scavenger of various ROS and a potent inhibitor of lipid peroxidation.46 This compound and its closely related derivatives have been widely used to study the effect of oxidative stress in a wide range of disorders.46 In addition, we have used this agent in our earlier studies demonstrating the role of oxidative stress in the pathogenesis of uremic and lead-induced hypertension.19 27
Antioxidant therapy significantly ameliorated hypertension and partially reversed the upregulation of NOS isotypes in various tissues of SHR. However, it did not fully restore either blood pressure or NOS isotype expression to the levels found in the normal control animals. Increased shear stress and cyclic strain upregulate eNOS expression. In addition, both systemic hypertension47 48 and regional cerebral arterial hypertension induced by simulated microgravity49 increase nNOS expression in the brain. Thus, the residual elevation of NOS isotype expression in the lazaroid-treated SHR may be due to the moderate hypertension observed in these animals. The partial role of elevated blood pressure in the upregulation of NOS isotypes is evidenced by significant but incomplete reversal of renal and vascular NOS isotype expressions with different antihypertensive agents (angiotensin type 1 receptor blockers and calcium channel blockers) in this model (X.Q. Wang, N.D. Vaziri, unpublished data, 2000). Thus, both ROS-mediated attenuation of negative-feedback regulation of NOS by NO and increased shear stress associated with hypertension contribute to the upregulation of NOS isotypes in SHR.
In conclusion, hypertension in untreated SHR was accompanied by increased urinary excretion of NO metabolites and marked upregulations of renal, vascular, and cardiac NOS isotype expression, confirming our earlier study.1 Administration of the potent antioxidant compound desmethyltirilazad ameliorated hypertension, lowered urinary NO metabolite excretion, and attenuated the compensatory upregulation of NOS isotypes in the tested organs. These findings point to the role of oxidative stress in the pathogenesis of hypertension and disordered NO metabolism in SHR.
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Acknowledgments |
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The authors wish to express their gratitude to Tania Tajalli for her assistance in this project.
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Footnotes |
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Reprint requests to N.D. Vaziri, MD, MACP, Division of Nephrology and Hypertension, UCI Medical Center, 101 The City Drive, Orange, CA 92868.
Received June 5, 2000; first decision June 30, 2000; accepted July 6, 2000.
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 H. S. Hwang, Y. S. Kim, Y. H. Ryu, J. E. Lee, Y. S. Lee, E. J. Yang, M. S. Lee, and S.-M. Choi Electroacupuncture Delays Hypertension Development through Enhancing NO/NOS Activity in Spontaneously Hypertensive Rats Evid. Based Complement. Altern. Med., October 7, 2008; (2008) nen064v1. [Abstract] [Full Text] [PDF]
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 H. Li, M. Hortmann, A. Daiber, M. Oelze, M. A. Ostad, P. M. Schwarz, H. Xu, N. Xia, A. L. Kleschyov, C. Mang, et al. Cyclooxygenase 2-Selective and Nonselective Nonsteroidal Anti-Inflammatory Drugs Induce Oxidative Stress by Up-Regulating Vascular NADPH Oxidases J. Pharmacol. Exp. Ther., September 1, 2008; 326(3): 745 - 753. [Abstract] [Full Text] [PDF]
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G. Cambonie, B. Comte, C. Yzydorczyk, T. Ntimbane, N. Germain, N. L. O. Le, P. Pladys, C. Gauthier, I. Lahaie, D. Abran, et al. Antenatal antioxidant prevents adult hypertension, vascular dysfunction, and microvascular rarefaction associated with in utero exposure to a low-protein diet Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2007; 292(3): R1236 - R1245. [Abstract] [Full Text] [PDF]
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 M. Franco, F. Martinez, B. Rodriguez-Iturbe, R. J. Johnson, J. Santamaria, A. Montoya, T. Nepomuceno, R. Bautista, E. Tapia, and J. Herrera-Acosta Angiotensin II, interstitial inflammation, and the pathogenesis of salt-sensitive hypertension Am J Physiol Renal Physiol, December 1, 2006; 291(6): F1281 - F1287. [Abstract] [Full Text] [PDF]
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A. Paliege, A. Parsumathy, D. Mizel, T. Yang, J. Schnermann, and S. Bachmann Effect of apocynin treatment on renal expression of COX-2, NOS1, and renin in Wistar-Kyoto and spontaneously hypertensive rats Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R694 - R700. [Abstract] [Full Text] [PDF]
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 T. Berg Increased counteracting effect of eNOS and nNOS on an {alpha}1-adrenergic rise in total peripheral vascular resistance in spontaneous hypertensive rats Cardiovasc Res, September 1, 2005; 67(4): 736 - 744. [Abstract] [Full Text] [PDF]
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N. D. Vaziri, Y. Ding, Z. Ni, and C. H. Barton Bradykinin Down-Regulates, Whereas Arginine Analogs Up-Regulates, Endothelial Nitric-Oxide Synthase Expression in Coronary Endothelial Cells J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 121 - 126. [Abstract] [Full Text] [PDF]
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S. Racasan, B. Braam, H. A. Koomans, and J. A. Joles Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon Am J Physiol Renal Physiol, April 1, 2005; 288(4): F626 - F636. [Abstract] [Full Text] [PDF]
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S. Adler and H. Huang Oxidant stress in kidneys of spontaneously hypertensive rats involves both oxidase overexpression and loss of extracellular superoxide dismutase Am J Physiol Renal Physiol, November 1, 2004; 287(5): F907 - F913. [Abstract] [Full Text] [PDF]
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 B. H. Jeon, G. Gupta, Y. C. Park, B. Qi, A. Haile, F. A. Khanday, Y.-X. Liu, J.-M. Kim, M. Ozaki, A. R. White, et al. Apurinic/Apyrmidinic Endonuclease 1 Regulates Endothelial NO Production and Vascular Tone Circ. Res., October 29, 2004; 95(9): 902 - 910. [Abstract] [Full Text] [PDF]
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 K. Sato, M. Kihara, T. Hashimoto, K. Matsushita, Y.-I. Koide, K. Tamura, N. Hirawa, Y. Toya, A. Fukamizu, and S. Umemura Alterations in Renal Endothelial Nitric Oxide Synthase Expression by Salt Diet in Angiotensin Type-1a Receptor Gene Knockout Mice J. Am. Soc. Nephrol., July 1, 2004; 15(7): 1756 - 1763. [Abstract] [Full Text] [PDF]
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 X. C. Wu and E. J. Johns Interactions between nitric oxide and superoxide on the neural regulation of proximal fluid reabsorption in hypertensive rats Exp Physiol, May 1, 2004; 89(3): 255 - 261. [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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S. Adler, H. Huang, M. S. Wolin, and P. M. Kaminski Oxidant Stress Leads to Impaired Regulation of Renal Cortical Oxygen Consumption by Nitric Oxide in the Aging Kidney J. Am. Soc. Nephrol., January 1, 2004; 15(1): 52 - 60. [Abstract] [Full Text] [PDF]
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 H. Negishi, J.-W. Xu, K. Ikeda, M. Njelekela, Y. Nara, and Y. Yamori Black and Green Tea Polyphenols Attenuate Blood Pressure Increases in Stroke-Prone Spontaneously Hypertensive Rats J. Nutr., January 1, 2004; 134(1): 38 - 42. [Abstract] [Full Text] [PDF]
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M. Nava, Y. Quiroz, N. Vaziri, and B. Rodriguez-Iturbe Melatonin reduces renal interstitial inflammation and improves hypertension in spontaneously hypertensive rats Am J Physiol Renal Physiol, March 1, 2003; 284(3): F447 - F454. [Abstract] [Full Text] [PDF]
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 S. Ulker, P. P. McKeown, and U. Bayraktutan Vitamins Reverse Endothelial Dysfunction Through Regulation of eNOS and NAD(P)H Oxidase Activities Hypertension, March 1, 2003; 41(3): 534 - 539. [Abstract] [Full Text] [PDF]
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J. Y.H. Chan, L.-L. Wang, Y.-M. Chao, and S. H.H. Chan Downregulation of Basal iNOS at the Rostral Ventrolateral Medulla Is Innate in SHR Hypertension, March 1, 2003; 41(3): 563 - 570. [Abstract] [Full Text] [PDF]
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A. Piech, C. Dessy, X. Havaux, O. Feron, and J.-L. Balligand Differential regulation of nitric oxide synthases and their allosteric regulators in heart and vessels of hypertensive rats Cardiovasc Res, February 1, 2003; 57(2): 456 - 467. [Abstract] [Full Text] [PDF]
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B. Rodriguez-Iturbe, C.-D. Zhan, Y. Quiroz, R. K. Sindhu, and N. D. Vaziri Antioxidant-Rich Diet Relieves Hypertension and Reduces Renal Immune Infiltration in Spontaneously Hypertensive Rats Hypertension, February 1, 2003; 41(2): 341 - 346. [Abstract] [Full Text] [PDF]
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V. Alvarez, Y. Quiroz, M. Nava, H. Pons, and B. Rodriguez-Iturbe Overload proteinuria is followed by salt-sensitive hypertension caused by renal infiltration of immune cells Am J Physiol Renal Physiol, November 1, 2002; 283(5): F1132 - F1141. [Abstract] [Full Text] [PDF]
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N. J. Schork, J. P. Gardner, L. Zhang, D. Fallin, B. Thiel, H. Jakubowski, and A. Aviv Genomic Association/Linkage of Sodium Lithium Countertransport in CEPH Pedigrees Hypertension, November 1, 2002; 40(5): 619 - 628. [Abstract] [Full Text] [PDF]
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 R. C. Sampaio, J. E. Tanus-Santos, S. E. S. F. C. Melo, S. Hyslop, K. G. Franchini, I. M. Luca, and H. Moreno Jr Hypertension Plus Diabetes Mimics the Cardiomyopathy Induced by Nitric Oxide Inhibition in Rats Chest, October 1, 2002; 122(4): 1412 - 1420. [Abstract] [Full Text] [PDF]
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S. Adler and H. Huang Impaired Regulation of Renal Oxygen Consumption in Spontaneously Hypertensive Rats J. Am. Soc. Nephrol., July 1, 2002; 13(7): 1788 - 1794. [Abstract] [Full Text] [PDF]
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X. J. Zhou, N. D. Vaziri, X. Q. Wang, F. G. Silva, and Z. Laszik Nitric Oxide Synthase Expression in Hypertension Induced by Inhibition of Glutathione Synthase J. Pharmacol. Exp. Ther., March 1, 2002; 300(3): 762 - 767. [Abstract] [Full Text] [PDF]
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T. Kishi, Y. Hirooka, K. Ito, K. Sakai, H. Shimokawa, and A. Takeshita Cardiovascular Effects of Overexpression of Endothelial Nitric Oxide Synthase in the Rostral Ventrolateral Medulla in Stroke-Prone Spontaneously Hypertensive Rats Hypertension, February 1, 2002; 39(2): 264 - 268. [Abstract] [Full Text] [PDF]
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N. D. Vaziri, Z. Ni, F. Oveisi, K. Liang, and R. Pandian Enhanced Nitric Oxide Inactivation and Protein Nitration by Reactive Oxygen Species in Renal Insufficiency Hypertension, January 1, 2002; 39(1): 135 - 141. [Abstract] [Full Text] [PDF]
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M.-G. Feng, S. A. W. Dukacz, and R. L. Kline Selective effect of tempol on renal medullary hemodynamics in spontaneously hypertensive rats Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2001; 281(5): R1420 - R1425. [Abstract] [Full Text] [PDF]
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X. Chen, R. M. Touyz, J. B. Park, and E. L. Schiffrin Antioxidant Effects of Vitamins C and E Are Associated With Altered Activation of Vascular NADPH Oxidase and Superoxide Dismutase in Stroke-Prone SHR Hypertension, September 1, 2001; 38(3): 606 - 611. [Abstract] [Full Text] [PDF]
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B. Rodriguez-Iturbe, Y. Quiroz, M. Nava, L. Bonet, M. Chavez, J. Herrera-Acosta, R. J. Johnson, and H. A. Pons Reduction of renal immune cell infiltration results in blood pressure control in genetically hypertensive rats Am J Physiol Renal Physiol, February 1, 2002; 282(2): F191 - F201. [Abstract] [Full Text] [PDF]
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