| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 1997;30:1628-1633.)
© 1997 American Heart Association, Inc.
Articles |
Oxidative Stress in the Dahl Hypertensive Rat
From the Department of Bioengineering and the Institute for Biomedical Engineering, University of California at San Diego (La Jolla).
Correspondence to Dr Geert W. Schmid-Schönbein, Institute for Biomedical Engineering, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0412. E-mail gwss{at}bioeng.ucsd.edu.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract Enhanced production of oxygen free radicals may play a role in hypertension by affecting vascular smooth muscle contraction, resistance to blood flow, and organ damage. The aim of this study was to determine whether oxygen free radicals are involved in the development of salt-induced hypertension. Dahl salt-sensitive (Dahl-S) and salt-resistant (Dahl-R) rats were fed either a high salt (6.0% NaCl) or low salt (0.3% NaCl) diet for 4 weeks. The high salt diet caused the development of severe hypertension in Dahl-S animals and had no effect on blood pressure in Dahl-R animals. A tetranitroblue tetrazolium dye was used to detect superoxide radicals in microvessels of the mesentery. Light absorption measurements revealed enhanced staining along the endothelium of arterioles and venules in hypertensive Dahl-S animals, with significantly lower values in normotensive animals. In addition, a Clark electrochemical electrode was used to measure hydrogen peroxide levels in fresh plasma. Hypertensive Dahl-S animals had a higher plasma hydrogen peroxide concentration compared with their normotensive counterparts (2.81±0.43 versus 2.10±0.41 µmol/L), while no difference was detected between high- and low salt–treated Dahl-R animals (1.70±0.35 versus 1.56±0.51 µmol/L). The plasma hydrogen peroxide levels of all groups correlated with mean arterial pressure (r=.77). These findings demonstrate an enhanced production of oxygen free radicals in the microvasculature of hypertensive Dahl-S rats.
Key Words: hypertension, salt-sensitive • free radicals • nitroblue tetrazolium • hydrogen peroxide • superoxides • rats, Dahl
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
An important unresolved issue in hypertension research is the mechanism for organ damage during the development of the syndrome. Reactive oxygen species such as superoxide radical (O2-), hydrogen peroxide (H2O2), and hydroxyl radical (·OH), may play a critical role in the pathogenesis of hypertension, as well as in other conditions such as atherosclerosis, stroke, and myocardial infarction.1 Oxygen free radicals may play a dual role. On one hand, they may affect vascular resistance by inactivating NO, thereby causing arteriolar vasoconstriction and elevation of peripheral hemodynamic resistance;2 on the other hand, they may serve as trigger mechanisms for lesion formation.
Recent studies by Prabha et al3 and Kumar and Das4 indicate that essential hypertension is associated with increased superoxide anion and hydrogen peroxide production by circulating leukocytes as well as decreased NO and antioxidant levels. They also showed that free radical production and NO levels in hypertensives reverted to normal values when treated with antihypertensive medication. In the genetic salt-sensitive Dahl hypertensive rat (Dahl-S), there is increasing evidence for a suppression of NO release, presumably from endothelial cells, which leads to constriction of peripheral arterioles and elevation of peripheral vascular resistance.5 There is also evidence that the Dahl-S has an elevated number of circulating leukocytes that produce superoxide compared with its normotensive control, the Dahl salt-resistant rat (Dahl-R).6 But no direct measurements of free radical production in the Dahl hypertensive model are available.
Thus, the purpose of this study was to study the involvement of oxygen radicals in the Dahl model of hypertension. In addition to hemodynamic and arteriolar tone measurements, we used tetranitroblue tetrazolium reduction as an index of spontaneous in vivo superoxide radical production in microvessels of the rat mesentery. Furthermore, we used a modification of the Clark electrode method to determine plasma hydrogen peroxide levels in Dahl-R and Dahl-S animals.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animals
All animal procedures were previously reviewed and approved by the University of California at San Diego Animal Subject Committee. Male Dahl-S and Dahl-R rats were obtained at 6 weeks of age from Harlan Sprague-Dawley (Indianapolis, Ind) and maintained on a diet of standard rat chow (0.3% NaCl) and water ad libitum for a 1-week observation period. The animals were then divided into four different diet groups as follows: Dahl-S, 0.3% NaCl control diet (n=9); Dahl-S, 6.0% NaCl enriched diet (n=12); Dahl-R, 0.3% NaCl control diet (n=7); and Dahl-R, 6.0% NaCl enriched diet (n=7). All animals were maintained on either the 0.3% NaCl control diet or the 6.0% NaCl enriched diet (ICN Nutritional Biochemicals) for 4 weeks. A femoral catheter (Clay Adams PE-50), was inserted for blood pressure measurements and blood sample withdrawal using 4% xylocaine (Astra USA Inc) as a local anesthetic. After the animals were allowed to recover from the surgical procedure, mean, systolic, and diastolic blood pressures and heart rate were continuously monitored in conscious animals via a transducer (Statham) for 30 minutes.
Intravital Microscopy
After administration of general anesthesia with
pentobarbital (50 mg/kg IV, Abbot Laboratories), rats were placed on a
heated stage. The abdomen was opened by a small midline incision, and
the ileocecal portion of the mesentery was gently exteriorized for
intravital microscopy as previously described.7 The
preparation was kept at 37°C and continuously superfused (1.0 mL/min)
with a Krebs-Henseleit bicarbonate-buffered solution saturated with a
95% N2 5% CO2 gas mixture. Special
precautions were taken to avoid interruption of the suffusate on the
tissue because even superficial drying causes rapid cell
injury.8
The mesenteric microcirculation was visualized through an intravital microscope (Technical Instruments) with the use of a digital color coupled charge device (CCD) camera (Optronics Engineering) and a 40x water immersion objective (Zeiss). Single unbranched vessels with diameter between 20 and 40 µm and length of approximately 150 µm were selected. The images were recorded with a videocassette recorder (Panasonic) for playback analysis.
Arteriolar Tone
In addition to steady state values, arterioles were studied
after local application of the vasodilator papaverine (1.0 mg/mL,
American Regent Laboratories). Measurements before and after
application of papaverine provided steady state lumen diameters
(Dss) and maximal diameters
(Dmax). All diameter measurements were measured
off-line using NIH Image 1.35 at constant central blood pressures
native to each animal. The tone (T) was computed as
T=(Dmax-Dss/Dmax)
and is a nondimensional parameter that specifies the degree
of active smooth muscle constriction such that T=0% in
dilated vessels and T=100% in fully constricted vessels
with an occluded lumen. No correction for the irregular shape of the
lumen cross section of contracting arterioles was
made.9
In Vivo Superoxide Production
Following the method of DeLano et al,10 TNBT
(Vector Laboratories) was used to detect superoxide radicals in vivo.
TNBT is reduced by superoxide radicals into the insoluble blue/black
product formazan. This reaction is specific for superoxide
radicals, since the reduction can be inhibited by superoxide
dismutase.11 TNBT was topically superfused over the
mesentery preparation for 1 hour. The preparation was then rinsed with
the superfusion buffer, fixed with formalin (Sigma Chemical), and
excised.
Whole-mount specimens were placed on a glass slide and viewed using a
laboratory microscope (Leitz) and 40x water immersion objective.
Images were digitized using a CCD camera and NIH Image 1.35. Using a
video photometric window (1x5 µm), a series of average
gray-value measurements were made along the endothelium
of mesenteric microvessels. As an index of superoxide formation,
measurements were expressed in terms of light absorption (A)
as
 |
Plasma Hydrogen Peroxide Production Levels
Blood samples were taken from the femoral arterial
catheter with 10 U/mL heparin as an anticoagulant (Pharmacia & Upjohn
Co), and immediately placed on ice (4°C) until measurements were
performed. All measurements were completed on samples within 2 to 3
hours, a period of time that did not significantly affect the peroxide
levels in these samples.
To measure hydrogen peroxide production levels, a 0.75-mL aliquot of anticoagulated blood was placed in a 2-mL centrifuge tube, incubated at 37°C for 10 minutes, and then centrifuged at 500g for 10 minutes. Thereafter, either sodium azide (NaN3; 10 µL of a 2-mol/L stock solution; Sigma Chemical) or catalase (10 µL containing 0.25 mg of the enzyme; Calbiochem) was added to the plasma layer and gently stirred. The Clark electrode was placed in the plasma of the aliquot (about 3 mm above the buffy coat), and its output was recorded for 10 minutes, at which point a steady electrode current was reached. Measurements were performed in duplicate, and the electrode was cleaned between measurements with a potent aqueous oxidizing solution (3% hydrogen peroxide; Fisher Scientific).12
Hydrogen peroxide was measured continuously with the electrode's
platinum anode, which was biased at 0.6 V with respect to the
silver/silver chloride cathode. Hydrogen peroxide is oxidized at the
surface of the anode according to the reaction
H2O2
O2+2H++2e-.
Because the output voltage generated by the electrode is not specific
for hydrogen peroxide, a differential measurement was carried out using
catalase and sodium azide. Catalase is an enzyme that which catalyzes
the reaction of hydrogen peroxide to oxygen and water
(2H2O2O2+2H2O) and
serves to eliminate hydrogen peroxide. Thus, the addition of catalase
provides a baseline or background current. In contrast, sodium azide
inhibits enzymes such as catalase and myeloperoxidase, which break down
hydrogen peroxide. Thus, the reading in a sample with azide gives the
current caused by hydrogen peroxide as well as the background. The
difference between these two currents provides a signal that is caused
by hydrogen peroxide alone. Calibration of the system was performed by
adding known concentrations of hydrogen peroxide to a buffered saline
solution and to plasma. A linear response was found in the range
between 0 and 10 µmol/L.
Statistical Analysis
Measurements are presented as the mean value±SD.
Unpaired comparisons between the 6.0% NaCl and 0.3% NaCl groups were
carried out by Student's t test. Analyses were
performed on Statworks 1.2. Values of P<.01 were considered
significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Blood Pressure
High salt–treated Dahl-S animals had substantially elevated mean, systolic, and diastolic blood pressures when compared with low salt–treated Dahl-S animals (P<.001; Table 1
). In contrast, the high salt diet
had no effect on blood pressure in Dahl-R animals. Hypertensive Dahl-S
animals also displayed a lower body weight and hematocrit compared to
its normotensive counterpart. Basal heart rates remained unchanged
among all groups.
|
In Vivo Superoxide
Light micrographs of TNBT-stained mesenteric arterioles and
venules are shown in Fig 1. Reduced TNBT,
in the form of blue/black formazan crystals, is seen along the
endothelium of vessels and not in the surrounding
interstitial space. Based on light absorption measurements,
high salt–treated Dahl-S arterioles stain 18% darker than low
salt–treated Dahl-S arterioles (Fig 2).
In contrast, only a 6% difference in staining level was detected
between high and low salt–treated Dahl-R arterioles. Similarly, high
salt–treated Dahl-S venules stained 15% darker than low salt–treated
Dahl-S venules, and no difference was detected between high and low
salt–treated Dahl-R venules. Invariably, TNBT staining in venules was
stronger than in arterioles.
|
|
indicates 0.3% NaCl; 
,
6.0% NaCl. *P<.001.
Plasma Hydrogen Peroxide Production
Hypertensive high salt–treated Dahl-S animals had a
significantly higher plasma hydrogen peroxide concentration when
compared with their normotensive low salt controls (2.81±0.43 versus
2.10±0.41 µmol/L; P<.01; Fig 3). In contrast, no plasma peroxide
difference was detected between high and low salt–treated Dahl-R
animals (1.70±0.35 versus 1.56±0.51 µmol/L), and both of these
animals had lower peroxide values than either Dahl-S animal. The plasma
hydrogen peroxide concentration showed a linear correlation with mean
arterial blood pressure in the four experimental groups
(r=.77, n=35; Fig 4).
|
P<.01.
|
,
Dahl-S, 0.3% NaCl; and 
, Dahl-S, 6.0% NaCl.
Arteriolar Tone
No difference in resting luminal diameter among the groups was
found. The resting diameters for high and low salt–treated Dahl-R and
high and low salt–treated Dahl-S animals were 17.6±4.0, 17.6±2.2,
18.6±3.5, and 18.5±4.6 µm, respectively. The arterioles of the
high salt–treated Dahl-S animals exhibited significantly higher tone
values than the low salt–treated Dahl-S animals (10.9±4.4 versus
3.0±0.9%; P<.001). In contrast, no difference was
detected between high and low salt–treated Dahl-R animals (3.0±1.2%
versus 3.6±0.5%). There was a positive linear correlation between
arteriolar tone and plasma peroxide concentration (r=.86,
n=35; Fig 5).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The question of whether elevated blood pressure alone constitutes a risk for cardiovascular complications in hypertensive subjects is unresolved. Few studies have provided a direct link between high blood pressure per se and the complications that accompany the hypertensive state, suggesting that direct treatment of elevated blood pressure may not necessarily address other factors in the development of the disease. The data in the literature provide no indication of the mechanisms that predispose hypertensives to organ injury.
Recently, we obtained direct evidence for a significant oxidative stress in the microvascular wall of spontaneously hypertensive rats (SHR) when compared with their normotensive control, the Wistar-Kyoto rat (WKY).13 Oxygen radicals are also produced spontaneously by circulating leukocytes of Dahl-S hypertensive rats but significantly less in leukocytes of their normotensive control, the Dahl-R rat.6 The present observations suggest that the progression of the hypertensive syndrome in the Dahl rat is also accompanied by overproduction of oxygen free radicals in the circulation.
It has been demonstrated in vivo that the establishment of salt-induced hypertension in the Dahl model is mediated by a suppression of basal NO synthesis/release5 and that flow-dependent vasodilation is modulated by salt intake even in Dahl-R rats.14 Moreover, hypertension in the Dahl model is preventable by administration of L-arginine, an NO donor.15 However, increasing evidence suggests that hypertension may be associated with increased decomposition of NO by superoxide and less by altered release of NO.16
In the SHR, the elevated production of oxygen free radicals involves an adrenal component, since adrenalectomy leads to a reduction of oxidative stress as well as arterial blood pressure.13 Administration of glucocorticoids to normotensive adrenalectomized SHR leads to return of the hypertensive state and elevated oxidative stress. There is also evidence to suggest that the Dahl hypertensive rat model involves an adrenal component.17 In fact, the involvement of mineralocorticoids in the development of salt-induced hypertension has been well characterized.18 19 20 However, the underlying mechanism that leads to the oxidative stress remains largely unexplored.
To understand the mechanism for oxygen free radical formation in hypertension, the cellular source must be identified. The endothelial cell, which is recognized as a source of NO, has also been identified as a potential source of oxygen free radical generation.21 22 Superoxide radicals in and around the vascular endothelial cells were found to play a critical role in the pathogenesis of hypertension. The present observations on the location of tetranitroblue tetrazolium reaction products, or formazan crystals, in the rat mesentery support the hypothesis that a major source of oxygen free radicals may be the endothelium of both the arterioles and venules. In addition, the increased staining in high salt–treated Dahl-S animals suggests that hypertension in the Dahl rat is associated with increased superoxide generation. Interestingly, the staining level in venules was higher than arterioles, the significance of which remains unknown. Other sources of oxygen free radicals could be circulating leukocytes6 and mitochondria.
The increase in plasma hydrogen peroxide concentration is most likely the result of the increase in superoxide. Because breakdown of superoxide, either spontaneously or via superoxide dismutase, leads to hydrogen peroxide, hydrogen peroxide levels may be used as a secondary, more stable indicator of oxidative stress. Not all superoxide radicals, however, are converted into hydrogen peroxide, since NO has been shown to be highly reactive with superoxide to form the stable product peroxynitrite (ONOO-).23 A higher arteriolar tone is associated with the increase in plasma hydrogen peroxide level in the high salt Dahl-S when compared with the low salt Dahl-S. The correlation between arteriolar tone and plasma hydrogen peroxide suggests that animals that have the highest plasma peroxide levels may also have arterioles in the most constricted state. At the same time, such animals may be subject to the largest oxidative stress, a condition that promotes the actual disease process by expression of inflammatory products, such as platelet activating factor, cytokines, and leukocyte adhesion molecules. The direct action of hydrogen peroxide on arteriolar tone is complex. Hydrogen peroxide has been shown to produce vasodilation in coronary arteries as well as cerebral and skeletal muscle arterioles.24 25 26 However, hydrogen peroxide has also been shown to produce vasoconstriction in carotid and pulmonary arteries.27 28 The response observed is often biphasic contraction after relaxation or vice versa and may be concentration dependent.
The in vivo TNBT assay is advantageous because it gives a visual display of oxidative stress within the microvascular network. However, superoxide is an unstable and short-lived radical, so detection errors may arise from reduction of TNBT independent of superoxide. For that reason, we also developed the assay for plasma hydrogen peroxide, a more stable oxygen species. A differential measurement, using catalase and sodium azide, was carried out because the output voltage generated by the electrode may also detect other species in plasma. The accuracy and stability of the hydrogen peroxide readings were confirmed by repeated measurements on a single sample. The second measurement differed from the first by only 5%, and the readings were stable over a 5-hour time period.
The relationship between oxygen free radicals and essential hypertension has received relatively limited attention. However, initial results suggest the trend that essential hypertension is associated with increased oxygen free radical production and decreased antioxidant capacity. Prabha et al3 demonstrated increased superoxide anion and hydrogen peroxide production by polymorphonuclear leukocytes of essential hypertensives; Kumar and Das4 showed decreased vitamin E and superoxide dismutase levels, and Tse et al29 showed decreased vitamin C and thiol levels in hypertensives. Thus, treatment directed at the oxygen free radical formation in addition to reduction of the central blood pressure may yield a benefit that remains to be explored.
The present observations may have other implications. The oxidative stress in hypertensives suggests not only that enhanced levels of oxygen radicals and deficiency of NO production may be responsible for the elevated tone in the arterioles and the elevated peripheral resistance, but that the oxidative stress also may be responsible for impaired endothelial cell function30 31 and enhanced vascular reactivity to different stimuli, such as oxygen.32 33
In summary, the present results suggest an enhanced production of superoxide radicals within the arterioles and venules of hypertensive Dahl-S animals. The endothelial cell appears to be one of the sources of this overproduction. Concomitant with the increase of superoxide production, there is an elevated level in plasma hydrogen peroxide and arteriolar tone.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This research was supported by National Institutes of Health grant HL-10881. The authors would also like to thank Dr Benjamin W. Zweifach for his advice and guidance.
Received October 7, 1996; first decision November 21, 1996; accepted June 16, 1997.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Halliwell B, Gutteridge JM. Free Radicals in Biology and Medicine. Oxford, UK: Clarendon Press; 1989.
2. Gryglewski RJ, Palmer RM, Moncada S. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature.. 1986;320:454-456.[Medline] [Order article via Infotrieve]
3. Prabha PS, Das UN, Koratkar R, Sagar PS, Ramesh G. Free radical generation, lipid peroxidation and essential fatty acids in uncontrolled essential hypertension. Prostaglandins Leukot Essent Fatty Acids.. 1990;41:27-33.[Medline] [Order article via Infotrieve]
4. Kumar KV, Das UN. Are free radicals involved in the pathobiology of human essential hypertension? Free Radic Res Commun.. 1993;19:59-66.[Medline] [Order article via Infotrieve]
5.
Boegehold MA. Reduced influence of nitric oxide
on arteriolar tone in hypertensive Dahl rats.
Hypertension.. 1992;19:290-295.
6.
Shen K, DeLano FA, Zweifach BW, Schmid-Schönbein
GW. Circulating leukocyte counts, activation, and degranulation
in Dahl hypertensive rats. Circ Res.. 1995;76:276-283.
7. Suematsu M, DeLano FA, Poole D, Engler RL, Miyasaka M, Zweifach BW, Schmid-Schönbein GW. Spatial and temporal correlation between leukocyte behavior and cell injury in postischemic rat skeletal muscle microcirculation. Lab Invest.. 1994;70:684-695.[Medline] [Order article via Infotrieve]
8. DeLano FA, Suematsu M, Zweifach BW, Schmid-Schönbein GW. Topography and onset of cell injury in exteriorized organ preparations using microfluorgraphy. FASEB J.. 1993;7:A882. Abstract.
9. Schmid-Schönbein GW, Murakami H. Blood flow in contracting arterioles. Int J Microcirc Clin Exp.. 1985;4:311-328.[Medline] [Order article via Infotrieve]
10. DeLano FA, Forrest MJ, Schmid-Schönbein GW. Attenuation of oxygen free radical formation and organ injury during experimental inflammation by P-selectin blockade. Microcirculation.. 1997;4:349-357.[Medline] [Order article via Infotrieve]
11. Beauchamp C, Fridovich I. Superoxide dismutase: improved assays and an assay applicable to acrylamide gels. Anal Biochem.. 1971;44:276-287.[Medline] [Order article via Infotrieve]
12. Feder DO, Koontz DE. Detection, removal, and control of organic contaminants in the production of electron devices. Symposium on Cleaning of Electronic Device Components and Materials.. 1959;246:40-63.
13.
Suzuki H, Swei A, Zweifach BW, Schmid-Schönbein
GW. In vivo evidence for microvascular oxidative stress in
spontaneously hypertensive rats: hydroethidine
microfluorography. Hypertension.. 1995;25:1083-1089.
14. Boegehold MA. Flow-dependent arteriolar dilation in normotensive rats fed low- or high-salt diets. Am J Physiol. 1995;H1407–1414.
15. Chen PY, Sanders PW. L-Arginine abrogates salt-sensitive hypertension in Dahl/Rapp rats. J Clin Invest.. 1991;88:1559-1567.
16.
Tschudi MR, Mesaros S, Luscher TF, Malinski T.
Direct in situ measurement of nitric oxide in mesenteric
resistance arteries: increased decomposition by superoxide in
hypertension. Hypertension.. 1996;27:32-35.
17. Iwai J, Knudsen KD, Dahl LK, Tassinari L. Effects of adrenalectomy on blood pressure in salt-fed, hypertension-prone rats: failure of hypertension to develop in absence of evidence of adrenal cortical tissue. J Exp Med.. 1969;129:663-678.[Abstract]
18.
Rapp JP, Dahl LK. Adrenal steroidogenesis in
rats bred for susceptibility and resistance to the hypertensive effect
of salt. Endocrinology.. 1971;88:52-65.
19. Rapp JP, Dahl LK. Possible role of 18-hydroxy-deoxycorticosterone in hypertension. Nature.. 1972;237:338-339.[Medline] [Order article via Infotrieve]
20. Rapp JP, Dahl LK. Mutant forms of cytochrome P-450 controlling both 18- and 11beta-steroid hydroxylation in the rat. Biochemistry.. 1976;15:1235-1242.[Medline] [Order article via Infotrieve]
21.
Nakazono K, Watanabe N, Matsuno K, Sasaki J, Sato T,
Inoue M. Does superoxide underlie the pathogenesis of
hypertension? Proc Natl Acad Sci U S A.. 1991;88:10045-10048.
22. 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;854-857.
23.
Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman
BA. Apparent hydroxyl radical production by
peroxynitrite: implications for endothelial injury from
nitric oxide and superoxide. Proc Natl Acad Sci
U S A.. 1990;87:1620-1624.
24. Bény JL, von der Weid PY. Hydrogen peroxide: an endogenous smooth muscle cell hyperpolarizing factor. Biochem Biophys Res Commun.. 1991;176:378-384.[Medline] [Order article via Infotrieve]
25. Wei EP, Kontos HA, Beckman JS. Mechanisms of cerebral vasodilation by superoxide, hydrogen peroxide, and peroxynitrite. Am J Physiol. 1996;H1262–1266.
26. Wolin MS, Rodenburg JM, Messina EJ, Kaley G. Oxygen metabolites and vasodilator mechanisms in rat cremasteric arterioles. Am J Physiol. 1987;H1159–1163.
27. Heinle H. Vasoconstriction of carotid artery induced by hydroperoxides. Arch Int Physiol Biochim.. 1984;92:267-271.[Medline] [Order article via Infotrieve]
28. Rhoades RA, Packer CS, Roepke DA, Jin N, Meiss RA. Reactive oxygen species alter contractile properties of pulmonary arterial smooth muscle. Can J Physiol Pharmacol.. 1990;68:1581-1589.[Medline] [Order article via Infotrieve]
29. Tse WY, Maxwell SR, Thomason H, Blann A, Thorpe GH, Waite M, Holder R. Antioxidant status in controlled and uncontrolled hypertension and its relationship to endothelial damage. J Hum Hypertens.. 1994;8:843-849.[Medline] [Order article via Infotrieve]
30.
Lombard JH, Hess ME, Stekiel WJ. Neural and
local control of arterioles in SHR. Hypertension.. 1984;6:530-535.
31. Boegehold MA. Effect of dietary salt on arteriolar nitric oxide in striated muscle of normotensive rats. Am J Physiol. 1993;H1810–1816.
32. Rafi JA, Boegehold MA. Microvascular responses to oxygen and muscle contraction in hypertensive Dahl rats. Int J Microcirc Clin Exp.. 1993;13:83-97.[Medline] [Order article via Infotrieve]
33. Lombard JH, Hess ME, Stekiel WJ. Enhanced response of arterioles to oxygen during development of hypertension in SHR. Am J Physiol. 1986;H761–H764.
This article has been cited by other articles:
 |
|
 |
|
  M. Kayikcioglu, M. Tumuklu, M. Ozkahya, O. Ozdogan, G. Asci, S. Duman, H. Toz, L. H. Can, A. Basci, and E. Ok The benefit of salt restriction in the treatment of end-stage renal disease by haemodialysis Nephrol. Dial. Transplant., March 1, 2009; 24(3): 956 - 962. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Macarthur, T. C. Westfall, and G. H. Wilken Oxidative stress attenuates NO-induced modulation of sympathetic neurotransmission in the mesenteric arterial bed of spontaneously hypertensive rats Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H183 - H189. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
N. Erdei, Z. Bagi, I. Edes, G. Kaley, and A. Koller H2O2 increases production of constrictor prostaglandins in smooth muscle leading to enhanced arteriolar tone in Type 2 diabetic mice Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H649 - H656. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
H. Matsui, T. Shimosawa, Y. Uetake, H. Wang, S. Ogura, T. Kaneko, J. Liu, K. Ando, and T. Fujita Protective Effect of Potassium Against the Hypertensive Cardiac Dysfunction: Association With Reactive Oxygen Species Reduction Hypertension, August 1, 2006; 48(2): 225 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Agarwal, K. C. Nandipati, R. K. Sharma, C. D. Zippe, and R. Raina Role of Oxidative Stress in the Pathophysiological Mechanism of Erectile Dysfunction J Androl, May 1, 2006; 27(3): 335 - 347. [Full Text] [PDF]
|
|
|
|
|
|
N. E. Taylor and A. W. Cowley Jr. Effect of renal medullary H2O2 on salt-induced hypertension and renal injury Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1573 - R1579. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Wilcox Oxidative stress and nitric oxide deficiency in the kidney: a critical link to hypertension? Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2005; 289(4): R913 - R935. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Kobayashi, F. A. DeLano, and G. W. Schmid-Schonbein Oxidative Stress Promotes Endothelial Cell Apoptosis and Loss of Microvessels in the Spontaneously Hypertensive Rats Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2114 - 2121. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhang, K. K. Griendling, A. Dikalova, G. K. Owens, and W. R. Taylor Vascular Hypertrophy in Angiotensin II-Induced Hypertension Is Mediated by Vascular Smooth Muscle Cell-Derived H2O2 Hypertension, October 1, 2005; 46(4): 732 - 737. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Vasdev, V. Gill, S. Parai, and V. Gadag Dietary Vitamin E Supplementation Attenuates Hypertension in Dahl Salt-Sensitive Rats Journal of Cardiovascular Pharmacology and Therapeutics, April 1, 2005; 10(2): 103 - 111. [Abstract] [PDF]
|
|
|
|
 |
|
 L. L. Howard, M. E. Patterson, J. J. Mullins, and K. D. Mitchell Salt-sensitive hypertension develops after transient induction of ANG II-dependent hypertension in Cyp1a1-Ren2 transgenic rats Am J Physiol Renal Physiol, April 1, 2005; 288(4): F810 - F815. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Drenjancevic-Peric and J. H. Lombard Reduced Angiotensin II and Oxidative Stress Contribute to Impaired Vasodilation in Dahl Salt-Sensitive Rats on Low-Salt Diet Hypertension, April 1, 2005; 45(4): 687 - 691. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. DeLano, R. Balete, and G. W. Schmid-Schonbein Control of oxidative stress in microcirculation of spontaneously hypertensive rats Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H805 - H812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 C. Cseko, Z. Bagi, and A. Koller Biphasic effect of hydrogen peroxide on skeletal muscle arteriolar tone via activation of endothelial and smooth muscle signaling pathways J Appl Physiol, September 1, 2004; 97(3): 1130 - 1137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Drenjancevic-Peric and J. H. Lombard Introgression of chromosome 13 in Dahl salt-sensitive genetic background restores cerebral vascular relaxation Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H957 - H962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Fries, P. Mahboubi, N. R. Mahapatra, S. K. Mahata, N. J. Schork, G. W. Schmid-Schoenbein, and D. T. O'Connor Neuroendocrine Transcriptome in Genetic Hypertension: Multiple Changes in Diverse Adrenal Physiological Systems Hypertension, June 1, 2004; 43(6): 1301 - 1311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kishi, Y. Hirooka, Y. Kimura, K. Ito, H. Shimokawa, and A. Takeshita Increased Reactive Oxygen Species in Rostral Ventrolateral Medulla Contribute to Neural Mechanisms of Hypertension in Stroke-Prone Spontaneously Hypertensive Rats Circulation, May 18, 2004; 109(19): 2357 - 2362. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. K Shieh, E. Kotlyar, and F. Sam Aldosterone and cardiovascular remodelling: focus on myocardial failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1): 3 - 13. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Galinanes and A. G Fowler Role of clinical pathologies in myocardial injury following ischaemia and reperfusion Cardiovasc Res, February 15, 2004; 61(3): 512 - 521. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Nishiyama, M. Yoshizumi, H. Hitomi, S. Kagami, S. Kondo, A. Miyatake, M. Fukunaga, T. Tamaki, H. Kiyomoto, M. Kohno, et al. The SOD Mimetic Tempol Ameliorates Glomerular Injury and Reduces Mitogen-Activated Protein Kinase Activity in Dahl Salt-Sensitive Rats J. Am. Soc. Nephrol., February 1, 2004; 15(2): 306 - 315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhu, T. Mori, T. Huang, and J. H. Lombard Effect of high-salt diet on NO release and superoxide production in rat aorta Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H575 - H583. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Vidrio, M. Medina, P. Gonzalez-Romo, M. Lorenzana-Jimenez, P. Diaz-Arista, and A. Baeza Semicarbazide-Sensitive Amine Oxidase Substrates Potentiate Hydralazine Hypotension: Possible Role of Hydrogen Peroxide J. Pharmacol. Exp. Ther., November 1, 2003; 307(2): 497 - 504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Fujii, L. Zhang, J. Igarashi, and H. Kosaka L-Arginine Reverses p47phox and gp91phox Expression Induced by High Salt in Dahl Rats Hypertension, November 1, 2003; 42(5): 1014 - 1020. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Dobrian, S. D. Schriver, T. Lynch, and R. L. Prewitt Effect of salt on hypertension and oxidative stress in a rat model of diet-induced obesity Am J Physiol Renal Physiol, October 1, 2003; 285(4): F619 - F628. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
M. Tepel Oxidative stress: does it play a role in the genesis of essential hypertension and hypertension of uraemia? Nephrol. Dial. Transplant., August 1, 2003; 18(8): 1439 - 1442. [Full Text] [PDF]
|
|
|
|
|
|
M. Tepel Oxidative stress: does it play a role in the genesis of essential hypertension and hypertension of uraemia? Nephrol. Dial. Transplant., August 1, 2003; 18(88): 1439 - 1442. [Full Text]
|
|
|
|
|
|
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]
|
|
|
|
|
|
S. Meng, G. W. Cason, A. W. Gannon, L. C. Racusen, and R. D. Manning Jr Oxidative Stress in Dahl Salt-Sensitive Hypertension Hypertension, June 1, 2003; 41(6): 1346 - 1352. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Chu, S. Iida, D. D. Lund, R. M. Weiss, G. F. DiBona, Y. Watanabe, F. M. Faraci, and D. D. Heistad Gene Transfer of Extracellular Superoxide Dismutase Reduces Arterial Pressure in Spontaneously Hypertensive Rats: Role of Heparin-Binding Domain Circ. Res., March 7, 2003; 92(4): 461 - 468. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
S. Meng, L. J. Roberts II, G. W. Cason, T. S. Curry, and R. D. Manning Jr. Superoxide dismutase and oxidative stress in Dahl salt-sensitive and -resistant rats Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2002; 283(3): R732 - R738. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
M. Rathaus and J. Bernheim Oxygen species in the microvascular environment: regulation of vascular tone and the development of hypertension Nephrol. Dial. Transplant., February 1, 2002; 17(2): 216 - 221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Lenda and M. A. Boegehold Effect of a high-salt diet on oxidant enzyme activity in skeletal muscle microcirculation Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H395 - H402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-L. Ma, F. Gao, A. H. Nelson, B. L. Lopez, T. A. Christopher, T.-L. Yue, and F. C. Barone Oxidative Inactivation of Nitric Oxide and Endothelial Dysfunction in Stroke-Prone Spontaneous Hypertensive Rats J. Pharmacol. Exp. Ther., September 1, 2001; 298(3): 879 - 885. [Abstract] [Full Text]
|
|
|
|
|
|
A. D. Dobrian, S. D. Schriver, and R. L. Prewitt Role of Angiotensin II and Free Radicals in Blood Pressure Regulation in a Rat Model of Renal Hypertension Hypertension, September 1, 2001; 38(3): 361 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. D. Vaziri, Y. Ding, and Z. Ni Compensatory Up-Regulation of Nitric-Oxide Synthase Isoforms in Lead-Induced Hypertension; Reversal by a Superoxide Dismutase-Mimetic Drug J. Pharmacol. Exp. Ther., August 1, 2001; 298(2): 679 - 685. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.-P. Zou, N. Li, and A. W. Cowley Jr. Production and Actions of Superoxide in the Renal Medulla Hypertension, February 1, 2001; 37(2): 547 - 553. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Dobrian, M. J. Davies, S. D. Schriver, T. J. Lauterio, and R. L. Prewitt Oxidative Stress in a Rat Model of Obesity-Induced Hypertension Hypertension, February 1, 2001; 37(2): 554 - 560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Beswick, H. Zhang, D. Marable, J. D. Catravas, W. D. Hill, and R. C. Webb Long-Term Antioxidant Administration Attenuates Mineralocorticoid Hypertension and Renal Inflammatory Response Hypertension, February 1, 2001; 37(2): 781 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. V. d'Uscio, T. Quaschning, J. C. Burnett Jr, and T. F. Luscher Vasopeptidase Inhibition Prevents Endothelial Dysfunction of Resistance Arteries in Salt-Sensitive Hypertension in Comparison With Single ACE Inhibition Hypertension, January 1, 2001; 37(1): 28 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. D. Vaziri, Z. Ni, F. Oveisi, and D. L. Trnavsky-Hobbs Effect of Antioxidant Therapy on Blood Pressure and NO Synthase Expression in Hypertensive Rats Hypertension, December 1, 2000; 36(6): 957 - 964. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Lacy, M. T. Kailasam, D. T. O'Connor, G. W. Schmid-Schonbein, and R. J. Parmer Plasma Hydrogen Peroxide Production in Human Essential Hypertension : Role of Heredity, Gender, and Ethnicity Hypertension, November 1, 2000; 36(5): 878 - 884. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Sauls and M. A. Boegehold Arteriolar wall PO2 and nitric oxide release during sympathetic vasoconstriction in the rat intestine Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H484 - H491. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Lenda, B. A. Sauls, and M. A. Boegehold Reactive oxygen species may contribute to reduced endothelium-dependent dilation in rats fed high salt Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H7 - H14. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ueno, P. Kanellakis, A. Agrotis, and A. Bobik Blood Flow Regulates the Development of Vascular Hypertrophy, Smooth Muscle Cell Proliferation, and Endothelial Cell Nitric Oxide Synthase in Hypertension Hypertension, July 1, 2000; 36(1): 89 - 96. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. D. Vaziri, X. Q. Wang, F. Oveisi, and B. Rad Induction of Oxidative Stress by Glutathione Depletion Causes Severe Hypertension in Normal Rats Hypertension, July 1, 2000; 36(1): 142 - 146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Dobrian, M. J. Davies, R. L. Prewitt, and T. J. Lauterio Development of Hypertension in a Rat Model of Diet-Induced Obesity Hypertension, April 1, 2000; 35(4): 1009 - 1015. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Griendling, D. Sorescu, and M. Ushio-Fukai NAD(P)H Oxidase : Role in Cardiovascular Biology and Disease Circ. Res., March 17, 2000; 86(5): 494 - 501. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Fujiwara, T. Osanai, T. Kamada, T. Katoh, K. Takahashi, and K. Okumura Study on the Relationship Between Plasma Nitrite and Nitrate Level and Salt Sensitivity in Human Hypertension : Modulation of Nitric Oxide Synthesis by Salt Intake Circulation, February 29, 2000; 101(8): 856 - 861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Kurose, R. Wolf, W. Cerwinka, and D. N. Granger Microvascular Responses to Ischemia/Reperfusion in Normotensive and Hypertensive Rats Hypertension, August 1, 1999; 34(2): 212 - 216. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Tritto and G. Ambrosio Spotlight on microcirculation: an update Cardiovasc Res, June 1, 1999; 42(3): 600 - 606. [Full Text] [PDF]
|
|
|
|
 |
|
 R. Ross Atherosclerosis -- An Inflammatory Disease N. Engl. J. Med., January 14, 1999; 340(2): 115 - 126. [Full Text] [PDF]
|
|
|
|
|
|
T. Marumo, V. B. Schini-Kerth, R. P. Brandes, and R. Busse Glucocorticoids Inhibit Superoxide Anion Production and p22 Phox mRNA Expression in Human Aortic Smooth Muscle Cells Hypertension, December 1, 1998; 32(6): 1083 - 1088. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Huang, D. Sun, G. Kaley, and A. Koller Superoxide Released to High Intra-arteriolar Pressure Reduces Nitric Oxide–Mediated Shear Stress– and Agonist-Induced Dilations Circ. Res., November 2, 1998; 83(9): 960 - 965. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Laakso, E. Mervaala, J.-J. Himberg, T.-L. Teravainen, H. Karppanen, H. Vapaatalo, and R. Lapatto Increased Kidney Xanthine Oxidoreductase Activity in Salt-Induced Experimental Hypertension Hypertension, November 1, 1998; 32(5): 902 - 906. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. D. Wang, D. G. Johns, S. Xu, and R. A. Cohen Role of superoxide anion in regulating pressor and vascular hypertrophic response to angiotensin II Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1697 - H1702. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||