This Article Abstract Full Text (PDF) All Versions of this Article: 46/4/1026    most recent 01.HYP.0000174989.39003.58v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kopkan, L. Articles by Majid, D. S. A. Search for Related Content PubMed PubMed Citation Articles by Kopkan, L. Articles by Majid, D. S. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Dietary Sodium High Blood Pressure Hazardous Substances DB HYDROGEN PEROXIDE NITRIC OXIDE PROSTAGLANDIN F2ALPHA

(Hypertension. 2005;46:1026.)
© 2005 American Heart Association, Inc.

Part 2 Original Articles

Superoxide Contributes to Development of Salt Sensitivity and Hypertension Induced by Nitric Oxide Deficiency

Libor Kopkan; Dewan S. A. Majid

From Department of Physiology, Tulane Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, La.

Correspondence to Dewan S.A. Majid, MD, PhD, Associate Professor, Department of Physiology, SL 39, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112. E-mail majid{at}tulane.edu

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
This study was performed to examine the role of superoxide (O₂^–) in the development of salt sensitivity and hypertension induced by inhibition of nitric oxide (NO) generation. Male Sprague-Dawley rats were fed with diet containing either normal salt (NS) (0.4% NaCl) or high salt (HS) (4% NaCl). These rats were treated with or without an NO synthase inhibitor, nitro-L-arginine methylester (L-NAME) (15 mg/kg/d) and O₂^– scavenger, tempol (30 mg/kg per day) in the drinking water for 4 weeks. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography and urine collection was performed during the course of experimental periods. At the end of 4 weeks, L-NAME treatment resulted in greater increases in SBP in HS rats (127±2 to 172±3 mm Hg; n=8) than in NS rats (130±2 to 156±2 mm Hg; n=9). Co-administration of tempol with L-NAME markedly attenuated these SBP responses to a similar level in both HS (128±3 to 147±2 mm Hg; n=8) and NS rats (126±2 to 142±3 mm Hg; n=8). Urinary 8-isoprostane excretion (U_IsoV) increased in response to L-NAME treatment that was higher in HS (10.6±0.5 to 21.5±0.8 ng/d) than in NS rats (10.8±0.7 to 16.9±0.6 ng/d). Co-treatment with tempol completely abolished these U_IsoV responses to L-NAME in both HS and NS rats but did not alter urinary H₂O₂ excretion rate. The decreases in urinary nitrate/nitrite excretion in response to L-NAME treatment were not altered by co-administration of tempol in both HS and NS rats. These data suggest that enhancement of O₂^– activity during NO inhibition contributes to the development of salt sensitivity that is associated with NO-deficient hypertension.

Key Words: hypertension • kidney • nitric oxide

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
Superoxide (O₂^–) and other reactive oxygen species are constant products of cellular metabolism. However, the development of oxidative stress is dependent on the balance between their production and degradation.^1,2 O₂^– is usually instantly reduced by the enzyme superoxide dismutase (SOD) normally present in living tissues.³ Nitric oxide (NO), another free radical, is also known to act as an antioxidative agent by constant elimination of O₂^– from the tissue, thus helping to maintain minimal level of O₂^– in normal condition and provides a protective function against the action of O₂^– in many organs including the kidney.^4–6 Thus, it is possible that in the condition of NO deficiency, there is an increasing accumulation of O₂^– in biological tissues.⁵ In fact, we have observed in an earlier study that acute NOS inhibition leads to enhanced O₂^– activity that exerts vasoconstriction, antidiuresis, and antinatriuresis effects in the kidney.^6,7 The results of these studies indicate that NO deficiency can lead to the development of oxidative stress in the body.

Oxidative stress has been suggested to be involved in the pathophysiology of many forms of hypertension;^8,9 however, the exact mechanism is not yet fully understood. Scavenging of O₂^– significantly reduces blood pressure in different models of hypertension,^10,11 especially those associated with salt-sensitivity.^12,13 Previous studies have indicated that inhibition of NO generation during high-salt intake leads to the development of salt-sensitive hypertension and the impairment of kidney function.^14–16 Thus, the increases in O₂^– level caused by NO deficiency may significantly contribute to the development of salt-sensitive forms of hypertension.

The specific aim of this study was to examine the role of O₂^– generation in the development of salt-sensitive hypertension during chronic nitric oxide synthase (NOS) inhibition in rats. To induce NO deficiency, chronic treatment with NOS inhibitor, nitro-L-arginine methyl ester (L-NAME) was given to rats during normal and high-salt intake.^14,17 Blood pressure and excretory responses were evaluated with or without co-treatment of O₂^– scavenger, tempol (4-hydroxy-tetramethylpiperidime-1-oxyl), during the course of 4-week treatment with L-NAME in these rats.^10,18,19

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
The study was performed in male Sprague-Dawley rats (Charles River Laboratories; Wilmington, Mass) in accordance with the guidelines and practices established by the Tulane University Animal Care and Use Committee. After 3 days of acclimatization, animals (220 to 250 grams body weight) were randomly divided into 6 experimental groups based on diet (normal salt, NS, 0.4% NaCl; or high-salt, HS, 4% NaCl; Harlan-Teklad, Madison, Wis) and drug treatment (NOS inhibitor, L-NAME, and O₂^– scavenger, tempol; Sigma, St. Louis, Mo): (1) NS, nontreated; (2) NS, L-NAME; (3) NS, L-NAME + tempol; (4) HS, nontreated; (5) HS, L-NAME; (6) HS, L-NAME + tempol. As in our pilot study, tempol treatment alone (n=2) was without any effect on blood pressure and, also, similar observation with chronic treatment of tempol was previously reported in normotensive rats;^10,11 we did not feel the necessity to repeat these experiments in the present study. Because control rats with HS intake also remained normotensive, we also did not conduct experiments with tempol treatment alone in these rats.

L-NAME at a dose of 15 mg/kg per day was given in drinking water for a 4-week experimental period. This dose of L-NAME was previously used by other investigators^14,17 as an adequate dose to achieve near-maximal inhibition of NOS in the body. Tempol was also added with L-NAME to the drinking water at a dose of 30 mg/kg per day as previously reported.^10,18,19 This dose of tempol was adequate to decrease blood pressure and plasma or urine 8-isoprostane levels in hypertensive rats.^10,18,19 Systolic blood pressure (SBP) was measured by tail-cuff plethysmography. Basal blood pressure was measured for 3 consecutive days before the starting the protocol and then at 3- to 4-day intervals during the 4-week study period. The 24-hour urine collection was performed in metabolic cages on the day before the start of treatment to establish basal excretory parameters and then on days 7, 14, 21, and 28 of experiment. Body weight and water intake were also recorded on each day of urine collections. The status of glomerular filtration rate (GFR) was assessed by calculating creatinine clearance to assess the differences in overall kidney function in these groups of experimental animals. To determine creatinine concentration in plasma samples, arterial blood samples were collected from a carotid arterial cannula placed in rats under anesthesia (pentobarbital, 50 mg/kg intraperitoneal).

Analytical Methods and Statistics
Urinary excretion of sodium and potassium were assessed by flame photometry. Concentration of 8-isoprostane in urine samples was determined by enzyme immunoassay (Cayman Chemical, Ann Arbor, Mich)^10,18 and H₂O₂ concentration was measured by colorimetric assay (Cayman Chemical).²⁰ Nitrate/nitrite (NOx) concentration was also measured colorimetrically (Assay Design, Ann Arbor, Mich).^6,20 To estimate glomerular filtration rate (GFR), creatinine clearance was calculated from the plasma and urine concentration determined colorimetrically. Results are expressed as mean±SEM. Statistical comparisons within groups were conducted by the use of ANOVA for repeated measurements, followed by Newman-Keuls test. Unpaired Student t test was used for comparisons between groups. Statistical significance is defined at a value of P=0.05.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Blood Pressure Responses
As shown in Figure 1, there were no significant differences in SBP at the end of 4-week experimental period in nontreated control groups with NS (127±2 to 133±2 mm Hg) or HS intake (129±2 to 136±3 mm Hg). These Sprague Dawley rats are normally not salt-sensitive as indicated by the fact that HS intake alone for 4 weeks did not significantly alter SBP. Chronic L-NAME treatment resulted in greater increases in SBP in HS rats (127±2 to 172±3 mm Hg; P<0.05) than in NS rats (130±2 to 156±2 mm Hg; P<0.05). Higher dose of L-NAME used in other studies in rats¹⁵ did not cause much difference in blood pressure responses compared with what we had observed in the present investigation indicating that this dose was sufficient to achieve a near maximal NOS inhibition. These data confirmed the previous observation^14–17 that NOS inhibition leads to a salt-sensitive model of hypertension. However, co-administration of tempol with L-NAME markedly attenuated SBP in both HS (128±3 to 147±2 mm Hg; P<0.05) as well as NS rats (126±2 to 142±3 mm Hg; P<0.05).

View larger version (19K): [in this window] [in a new window]   Figure 1. Blood pressure responses to chronic L-NAME and Tempol (T) treatment during normal or high salt intake. *P<0.05 vs nontreated group; #P<0.05 vs L-NAME group.

Excretory Responses
Urine volumes collected for 24 hours are given in the Table. In addition, recorded body weight and 24-hour water intake are also given in the Table. It was observed that an age-related weight gains in these animals were slightly less in L-NAME–treated animals compared with untreated group in both NS- and HS-fed rats. Such a slight decrease in weight gain was not seen in groups of rats co-treated with tempol. Thus, the retention of sodium caused by L-NAME administration did not cause any weight gains in these groups of animals. We also observed that the water intake was mostly remained unchanged during L-NAME or L-NAME plus tempol treatment though generally HS intake groups showed higher water intake compared with NS groups as expected (Table).

View this table: [in this window] [in a new window]   Body Weight, Water Intake, and Urine Volume During 4-Week Experimental Period

The responses in urinary excretion rate of NO metabolites, nitrate/nitrite (U_NOxV), to treatment with L-NAME and tempol in these experimental animals are shown in Figure 2. As expected, U_NOxV was significantly lower in L-NAME–treated animals in both NS (21.1±1.2 to 14.8±0.9 µmol/d) and HS intake groups (21.8±1.6 to 11.7±0.7 µmol/d). Co-treatment with tempol did not alter the observed reduction in U_NOxV induced by inhibition of NO generation either in the NS (15.6±1.3 µmol/d) or in the HS group (13.5±0.9 µmol/d). As shown in Figure 3, urinary 8-isoprostane excretion (U_ISOV) caused by chronic L-NAME treatment for 4 weeks was significantly higher in both NS (16.9±0.3 ng/d) and HS (21.5±0.8 ng/d) groups compared with corresponding NS (12.5±0.7 ng/d) and HS (13.7±0.9 ng/d) control group, indicating that NO deficiency leads to higher O₂^– activity. However, co-administration of tempol completely abolished U_ISOV responses to L-NAME in both NS (13.8±0.7 ng/d) and HS (15.8±0.9 ng/d) groups, indicating that the dose of tempol effectively reduces O₂^– activity in these rats during NOS inhibition. In NS rats, L-NAME treatment caused slightly but significantly lower sodium excretion on days 21 and 28 compared with the NS nontreated rats (Figure 4A). In the NS L-NAME plus tempol-treated group, sodium excretion was higher compared with the NS L-NAME–treated group. HS intake caused expected increases in sodium excretion compared with NS groups (Figure 4B). However, in the HS L-NAME group, sodium excretion was significantly lower on days 7, 14, and 21 compared with the HS nontreated group. In the HS L-NAME plus tempol-treated group, sodium excretion was significantly higher than that in the HS L-NAME group.

View larger version (19K): [in this window] [in a new window]   Figure 2. Urinary nitrate/nitrite excretion responses to chronic L-NAME and Tempol (T) treatment during normal or high salt intake. *P<0.05 vs nontreated group.

View larger version (16K): [in this window] [in a new window]   Figure 3. Urinary 8-isoprostane excretion responses to chronic L-NAME and Tempol (T) treatment during normal or high salt intake. *P<0.05 vs nontreated group; #P<0.05 vs L-NAME group.

View larger version (15K): [in this window] [in a new window]   Figure 4. Urinary sodium excretion responses to chronic L-NAME and Tempol (T) treatment during normal or high salt intake. *P<0.05 vs nontreated group; #P<0.05 vs L-NAME group.

The urinary excretion rate of H₂O₂ (U_H2O2V) was determined in the samples collected from the experimental animals at the end of week 4 of treatment period. The results are illustrated in Figure 5. We observed that administration of L-NAME did not alter U_H2O2V significantly in these rats fed NS or HS diets. Co-administration of tempol with L-NAME did not cause any significant increase in U_H2O2V in both HS and NS groups. However, it was observed that U_H2O2V was higher in nontreated HS group of rats compared with that in nontreated NS groups as reported earlier in another study.²¹

View larger version (13K): [in this window] [in a new window]   Figure 5. Urinary H2O2 excretion rate responses to chronic L-NAME and Tempol (T) treatment measured at the end of experimental period in normal or high salt groups (only the values from urine samples collected at day 28 were used here).

At the end of 4 weeks, creatinine clearance was calculated to determine the changes in estimated GFR (Figure 6). Attenuated creatinine clearances caused by chronic L-NAME treatment in both NS and HS rats compared with nontreated groups were partially restored in groups co-treated with tempol, suggesting that the decrease in GFR during NOS blockade is partly caused by enhancement of O₂^– activity in the kidney.

View larger version (15K): [in this window] [in a new window]   Figure 6. Creatinine clearance responses to chronic L-NAME and Tempol (T) treatment during normal or high-salt intake. *P<0.05 vs nontreated group; #P<0.05 vs L-NAME group.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
In the present investigation, it was observed that scavenging of O₂^– by chronic tempol administration attenuated the SBP response to chronic L-NAME administration in rats during NS as well as HS intake. However, SBP during co-treatment of L-NAME and tempol remained significantly higher than that in the nontreated control groups (Figure 1). Urinary excretion rate of sodium was seen lower in L-NAME–treated rats but not in tempol co-treated rats in both NS and HS intake groups (Figure 4). The decreases in creatinine clearance (GFR) in L-NAME–treated rats were seen partially restored by co-treatment of tempol (Figure 6). Such decreases in GFR in L-NAME–treated groups were caused presumably caused by increases in pre-glomerular arteriolar resistances by the lack of NO production.² However, partial restoration of GFR during co-treatment with tempol indicated that an enhancement of O₂^– caused by NOS inhibition also played a role in such increases in pre-glomerular resistances as suggested in earlier studies.^2,22 Thus, the findings in the present study have indicated that an enhanced O₂^– activity modulates both renal hemodynamics and excretory function in the condition of NO deficiency that may be involved in the development of hypertension induced by NOS inhibition.

It has been demonstrated that NOS inhibition enhances vascular O₂^– release both in rats^23,24 and in humans,²⁵ and such enhanced O₂^– production was abolished by the use of a O₂^– scavenger.²⁵ Although we did not measure directly the O₂^– level in the present study, we observed that U_ISOV (a marker for endogenous O₂^– activity) increased in L-NAME–treated rats and the response was greater in the HS group of rats compared with that in the NS group (Figure 3). These U_ISOV responses to L-NAME were completely prevented in rats co-treated with tempol indicating an increase in O₂^– activity during NOS inhibition. In our previous studies in dogs,^6,20 we also observed an increase in U_ISOV during acute NOS inhibition in the kidney that was ameliorated by co-administration of tempol.

Although L-NAME–induced SBP response was much greater in the HS intake group compared with the NS intake group, tempol treatment caused attenuation of SBP to similar levels in both groups that are not significantly different from each other (Figure 1). Because tempol administration abolished the differences in hypertensive responses to L-NAME during varying salt intake, these findings indicate that the development of salt-sensitivity induced by chronic NOS inhibition is mainly attributed to increases in endogenous O₂^– activity. Tempol treatment did not alter U_NOxV in the NOS inhibited rats, indicating that the blood pressure lowering effect of tempol in the present study was not caused by reversal of NO bioavailability but rather was caused by decreases in O₂^– activity. It has also been shown that tempol treatment significantly attenuates blood pressure in several hypertensive models that are particularly associated with salt-sensitivity.^12,13,18,26 Thus, the results of present investigation further support an important role of O₂^– in the development of salt-sensitivity in NO-deficient hypertension.

It may be argued that tempol as a SOD mimetic lead to increases in H₂O₂ levels that influence the SBP responses in rats in the present investigation. However, it was observed that tempol administration in L-NAME–treated rats did not cause any significant increase in U_H2O2V in both HS and NS groups (Figure 5). Thus, it would argue against any significant contribution of H₂O₂ in the observed marked attenuation of the SBP responses to tempol in L-NAME–treated rats. Although the effects of catalase administration after tempol treatment had not been examined in the present study, we have reported earlier that acute administration of tempol did not alter U_H2O2V either in dogs²⁰ or in normotensive, as well as angiotensin II–induced hypertensive rats.²⁷ We also observed that there was no significant difference between the renal responses to intra-arterial administration of tempol with or without catalase in rats.²⁷ As reported previously,²¹ U_H2O2V was seen higher in nontreated HS group of rats compared with that in nontreated NS groups in our present study. It is to be noted here that such differences in U_H2O2V was observed, although blood pressure levels are similar in both nontreated NS and HS groups. However, the effects of a possible change in vascular level of H₂O₂ during tempol administration are yet to be determined conclusively.^{21,24,28–30} It has been shown that H₂O₂ acts as a vasodilator,^24,30 implicating that enhancement of its vascular level would cause a decrease in blood pressure. However, some studies have implicated that increases in renal medullary tissue H₂O₂ level causes hypertension in rats,^28,29 an effect that is opposite to the present finding of tempol-induced reduction in SBP.

Oxidative stress and hypertension are closely associated with higher sympathetic activity.^31,32 Thus, it could be argued that tempol-induced changes in blood pressure observed in the present study may be influenced by its inhibitory effects on sympathetic activity³² or antioxidant-induced changes in the release of norepinephrine from the nerve terminals.³³ However, it was also demonstrated that enhanced O₂^– activity by SOD inhibition can cause stimulation of sympathetic activity that was shown to be inhibited by tempol.³⁴ Thus, reduction of endogenous O₂^– activity by tempol administration can indirectly be associated with a possible reduction in sympathetic activity in hypertensive rats in the present study.

The exact mechanism that produces increases in the endogenous level of O₂^– during NOS inhibition is not yet clear. Both NO and O₂^– are constant products of cellular metabolism, and both of these molecules are constantly interacting with each other in biological tissues.⁵ Normally, O₂^– in the tissue is kept to a minimal level by the antioxidative function of SOD as well as NO. However, when NO production is diminished in the tissue, it is expected that this balance may be altered allowing O₂^– accumulation in the tissue because of its inadequate removal by NO.⁶ It is also possible that the activity of enzymes responsible for endogenous production of O₂^– may be upregulated during NOS inhibition.³⁵ Further experiments are required to determine the activity of these oxidative enzymes during NO synthase inhibition.

In conclusion, these data demonstrate that the enhanced O₂^– activity caused by chronic NOS inhibition contributes to the development of salt sensitivity that is involved in the pathophysiology of the NO-deficient form of hypertension.

Perspectives
The findings of this present study further support our previous observations indicating an important role of the interaction between O₂^– and NO in the regulation of renal function and blood pressure.^4–9 NO provides a protective role against the actions of O₂^– by acting as an important antioxidative agent in the body. The development of any imbalance between oxidative and antioxidative processes in living tissues would lead to derangements in organ function including the kidney. The results of the present study, which demonstrate a close relation between enhancement of O₂^– activity and the development of salt sensitivity during NOS inhibition, provide an important clue in our quest in understanding the pathophysiology of salt-sensitive hypertension. Thus, it is imperative that further emphasis should be focused on complete elucidation of the interactive role of O₂^– and NO in the regulation of many organ functions to increase our knowledge on physiology as well as pathophysiologic processes of many diseases that are linked to NO metabolism and oxidative stress.

	Acknowledgments

 
We gratefully acknowledge the technical help provided by Alexander Castillo and Kevin Wellen.

This study was supported by National Heart, Lung, and Blood Institute grant HL-51306.

Received April 28, 2005; first decision May 15, 2005; accepted June 13, 2005.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res. 2000; 87: 840–844.[Abstract/Free Full Text]
2. Wilcox CS. Redox regulation of the afferent arteriole and tubuloglomerular feedback. Acta Physiol Scand. 2003; 179: 217–223.[CrossRef][Medline] [Order article via Infotrieve]
3. Kitiyakara C, Chabrashvili T, Chen Y, Blau J, Karber A, Aslam S, Welch WJ, Wilcox CS. Salt intake, oxidative stress, and renal expression of NADPH oxidase and superoxide dismutase. J Am Soc Nephrol. 2003; 14: 2775–2782.[Abstract/Free Full Text]
4. Touyz RM. Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension:what is the clinical significance? Hypertension. 2004; 44: 248–252.[Abstract/Free Full Text]
5. Modlinger PS, Wilcox CS, Aslam S. Nitric oxide, oxidative stress, and progression of chronic renal failure. Semin Nephrol. 2004; 24: 354–365.[CrossRef][Medline] [Order article via Infotrieve]
6. Majid DSA, Nishiyama A, Jackson KE, Castillo A. Inhibition of nitric oxide synthase enhances superoxide activity in canine kidney. Am J Physiol Regul Integr Comp Physiol. 2004; 287: R27–R32.[Abstract/Free Full Text]
7. Majid DSA, Nishiyama A. Nitric oxide blockade enhances renal responses to superoxide dismutase inhibition in dogs. Hypertension. 2002; 39: 293–297.[Abstract/Free Full Text]
8. Romero JC, Reckelhoff JF. Role of angiotensin and oxidative stress in essential hypertension. Hypertension. 1999; 34: 943–949.[Abstract/Free Full Text]
9. Wilcox CS. Reactive oxygen species: roles in blood pressure and kidney function. Curr Hypertens Rep. 2002; 4: 160–166.[Medline] [Order article via Infotrieve]
10. Schnackenberg CG, Wilcox CS. Two-week administration of tempol attenuates both hypertension and renal excretion of 8-iso prostaglandin f2alpha. Hypertension. 1999; 33: 424–428.[Abstract/Free Full Text]
11. Welch WJ, Blau J, Xie H, Chabrashvili T, Wilcox CS. Angiotensin-induced defects in renal oxygenation: role of oxidative stress. Am J Physiol Heart Circ Physiol. 2005; 288: H22–H28.[Abstract/Free Full Text]
12. Manning RD Jr, Meng S, Tian N. Renal and vascular oxidative stress and salt-sensitivity of arterial pressure. Acta Physiol Scand. 2003; 179: 243–250.[CrossRef][Medline] [Order article via Infotrieve]
13. Howard LL, Patterson ME, Mullins JJ, Mitchell KD. Salt-sensitive hypertension develops after transient induction of ANG II-dependent hypertension in Cyp1a1-Ren2 transgenic rats. Am J Physiol Renal Physiol. 2005; 288: F810–F815.[Abstract/Free Full Text]
14. Tolins JP, Shultz PJ. Endogenous nitric oxide synthesis determines sensitivity to the pressor effect of salt. Kidney Int. 1994; 46: 230–236.[Medline] [Order article via Infotrieve]
15. Yamada SS, Sassaki AL, Fujihara CK, Malheiros DM, De Nucci G, Zatz R. Effect of salt intake and inhibitor dose on arterial hypertension and renal injury induced by chronic nitric oxide blockade. Hypertension. 1996; 27: 1165–1172.[Abstract/Free Full Text]
16. Nakanishi K, Hara N, Nagai Y. Salt-sensitive hypertension in conscious rats induced by chronic nitric oxide blockade. Am J Hypertens. 2002; 15: 150–156.[CrossRef][Medline] [Order article via Infotrieve]
17. Scrogin KE, Hatton DC, Chi Y, Luft FC. Chronic nitric oxide inhibition with L-NAME: effects on autonomic control of the cardiovascular system. Am J Physiol. 1998; 274: R367–R374.[Medline] [Order article via Infotrieve]
18. Hoagland KM, Maier KG, Roman RJ. Contributions of 20-HETE to the antihypertensive effects of tempol in Dahl salt-sensitive rats. Hypertension. 2003; 41: 697–702.[Abstract/Free Full Text]
19. Zhang Y, Croft KD, Mori TA, Schyvens CG, McKenzie KU, Whitworth JA. The antioxidant tempol prevents and partially reverses dexamethasone-induced hypertension in the rat. Am J Hypertens. 2004; 17: 260–265.[CrossRef][Medline] [Order article via Infotrieve]
20. Majid DS, Nishiyama A, Jackson KE, Castillo A. Superoxide scavenging attenuates renal responses to ANG II during nitric oxide synthase inhibition in anesthetized dogs. Am J Physiol Renal Physiol. 2005; 288: F412–F419.[Abstract/Free Full Text]
21. Williams JM, Pollock JS, Pollock DM. Arterial pressure response to the antioxidant tempol and ETB receptor blockade in rats on a high-salt diet. Hypertension. 2004; 44: 770–775.[Abstract/Free Full Text]
22. Haque MZ, Majid DS. Assessment of renal functional phenotype in mice lacking gp91PHOX subunit of NAD(P)H oxidase. Hypertension. 2004; 43: 335–340.[Abstract/Free Full Text]
23. Usui M, Egashira K, Kitamoto S, Koyanagi M, Katoh M, Kataoka C, Shimokawa H, Takeshita A. Pathogenic role of oxidative stress in vascular angiotensin-converting enzyme activation in long-term blockade of nitric oxide synthesis in rats. Hypertension. 1999; 34: 546–551.[Abstract/Free Full Text]
24. Cosentino F, Barker JE, Brand MP, Heales SJ, Werner ER, Tippins JR, West N, Channon KM, Volpe M, Luscher TF. Reactive oxygen species mediate endothelium-dependent relaxations in tetrahydrobiopterin-deficient mice. Arterioscler Thromb Vasc Biol. 2001; 21: 496–502.[Abstract/Free Full Text]
25. Guzik TJ, West NE, Pillai R, Taggart DP, Channon KM. Nitric oxide modulates superoxide release and peroxynitrite formation in human blood vessels. Hypertension. 2002; 39: 1088–1094.[Abstract/Free Full Text]
26. Park JB, Touyz RM, Chen X, Schiffrin EL. Chronic treatment with a superoxide dismutase mimetic prevents vascular remodeling and progression of hypertension in salt-loaded stroke-prone spontaneously hypertensive rats. Am J Hypertens. 2002; 15: 78–84.[CrossRef][Medline] [Order article via Infotrieve]
27. Kopkan L, Castillo A, Navar LG, Majid DS. Renal hemodynamic and excretory response to superoxide anion scavenging in angiotensin II-induced hypertensive rats. J Am Soc Nephrol. 2004; 15: 207A. Abstract.
28. Makino A, Skelton MM, Zou AP, Cowley AW Jr. Increased renal medullary H2O2 leads to hypertension. Hypertension. 2003; 42: 25–30.[Abstract/Free Full Text]
29. Chen YF, Cowley AW Jr, Zou AP. Increased H2O2 counteracts the vasodilator and natriuretic effects of superoxide dismutation by tempol in renal medulla. Am J Physiol Regul Integr Comp Physiol. 2003; 285: R827–R833.[Abstract/Free Full Text]
30. Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE, Harrison DG. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest. 2003; 111: 1201–1209.[CrossRef][Medline] [Order article via Infotrieve]
31. Campese VM, Ye S, Zhong H, Yanamadala V, Ye Z, Chiu J. Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity. Am J Physiol Heart Circ Physiol. 2004; 287: H695–H703.[Abstract/Free Full Text]
32. Xu H, Fink GD, Galligan JJ. Tempol lowers blood pressure and sympathetic nerve activity but not vascular O₂^– in DOCA-salt rats. Hypertension. 2004; 43: 329–334.[Abstract/Free Full Text]
33. Jou SB, Cheng JT. The role of free radicals in the release of noradrenaline from myenteric nerve terminals of guinea-pig ileum. J Auton Nerv Syst. 1997; 66: 126–130.[CrossRef][Medline] [Order article via Infotrieve]
34. Shokoji T, Fujisawa Y, Kimura S, Rahman M, Kiyomoto H, Matsubara K, Moriwaki K, Aki Y, Miyatake A, Kohno M, Abe Y, Nishiyama A. Effects of local administrations of tempol and diethyldithio-carbamic on peripheral nerve activity. Hypertension. 2004; 44: 236–243.[Abstract/Free Full Text]
35. Husain K, Hazelrigg SR. Oxidative injury due to chronic nitric oxide synthase inhibition in rat: effect of regular exercise on the heart. Biochim Biophys Acta. 2002; 1587: 75–82.[Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				M. L. Graciano, C. R. Mouton, M. E. Patterson, D. M. Seth, J. J. Mullins, and K. D. Mitchell Renal vascular and tubulointerstitial inflammation and proliferation in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension Am J Physiol Renal Physiol, June 1, 2007; 292(6): F1858 - F1866. [Abstract] [Full Text] [PDF]

				N. J. Hong and J. L. Garvin Flow increases superoxide production by NADPH oxidase via activation of Na-K-2Cl cotransport and mechanical stress in thick ascending limbs Am J Physiol Renal Physiol, March 1, 2007; 292(3): F993 - F998. [Abstract] [Full Text] [PDF]

				L. Kopkan, A. Castillo, L. G. Navar, and D. S. A. Majid Enhanced superoxide generation modulates renal function in ANG II-induced hypertensive rats Am J Physiol Renal Physiol, January 1, 2006; 290(1): F80 - F86. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 46/4/1026    most recent 01.HYP.0000174989.39003.58v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kopkan, L. Articles by Majid, D. S. A. Search for Related Content PubMed PubMed Citation Articles by Kopkan, L. Articles by Majid, D. S. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Dietary Sodium High Blood Pressure Hazardous Substances DB HYDROGEN PEROXIDE NITRIC OXIDE PROSTAGLANDIN F2ALPHA