This Article Abstract Full Text (PDF) All Versions of this Article: 42/4/806    most recent 01.HYP.0000084372.91932.BAv1 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 Sedeek, M. H. Articles by Granger, J. P. Search for Related Content PubMed PubMed Citation Articles by Sedeek, M. H. Articles by Granger, J. P. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information High Blood Pressure Hazardous Substances DB PROSTAGLANDIN F2ALPHA Related Collections Animal models of human disease

(Hypertension. 2003;42:806.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Role of Reactive Oxygen Species in Endothelin-Induced Hypertension

Mona H. Sedeek; Maria T. Llinas; Heather Drummond; Lourdes Fortepiani; Sean R. Abram; Barbara T. Alexander; Jane F. Reckelhoff; Joey P. Granger

From the Department of Physiology and Biophysics, Center for Excellence in Cardiovascular–Renal Research, University of Mississippi Medical Center, Jackson, Miss.

Correspondence to Joey P. Granger, PhD, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216-4505. E-mail jgranger{at}physiology.umsmed.edu

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Recent reports have indicated that endothelin-induced vasoconstriction in isolated aortic vascular rings may be mediated by the production of superoxide anion. The purpose of this study was to determine the role of superoxide anion in mediating the chronic renal and hypertensive actions of endothelin. Endothelin-1 (5 pmol/kg per minute) was chronically infused into the jugular vein by use of mini-osmotic pump for 9 days in male Sprague-Dawley rats and in rats treated with the superoxide anion scavenger tempol (30 mg/kg per day). Mean arterial pressure in the endothelin-1–treated rats was 141±3 mm Hg, compared with 125±2 mm Hg in control rats. Endothelin-1 increased renal vascular resistance (15.3±2.5 versus 10±1.3 mm Hg/mL per minute) and decreased renal plasma flow (6.5±0.9 versus 8.7±0.7 mL/min) in control rats. Endothelin-1 also significantly increased TBARS in the kidney and urinary 8-isoprostaglandin F₂ excretion. The increase in arterial pressure in response to endothelin-1 was completely abolished by tempol (127±4 versus 127±4 mm Hg). Tempol also markedly attenuated the renal plasma flow and renal vascular resistance response to endothelin-1. Tempol also significantly decreased the level of 8-isoprostaglandin F₂ in the endothelin-1–treated rats. Tempol had no effect on arterial pressure or renal hemodynamics in control rats. These data indicate that formation of reactive oxygen species may play an important role in mediating hypertension induced by chronic elevations in endothelin.

Key Words: endothelin • hypertension, chronic • vasoconstriction • anions • hemodynamics

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Endothelin, a 21–amino acid peptide, has potent and sustained vasoconstrictive effects on vascular smooth muscle both in vivo and in vitro.¹ Three mature (21-residue) endothelin isoforms (ET-1, ET-2, and ET-3) are encoded in human, rat, and pig genomes, of which the most potent isoform, endothelin-1, is synthesized by the endothelium.¹ Endothelin-1 has been shown to result in an elevation of mean arterial pressure (MAP) in conscious animals.^{2, 3} Additionally, endothelin-induced hypertension has been associated with an increase in total peripheral resistance and renal vascular resistance (RVR), an effect that is dose-dependent in dogs and rats.^2,3 Endothelin-1 also decreases both renal plasma flow (RPF) and glomerular filtration rate (GFR) through vasoconstriction of the glomerular afferent and efferent arterioles.⁴ A role for endogenous endothelin in mediating the renal and systemic cardiovascular alteration in various forms of hypertension has also been suggested.¹

Recent reports have indicated that endothelin-induced vasoconstriction may be mediated by the production of superoxide anion.^5,6 In vitro studies have shown that the increased superoxide anion production observed in cells treated with cyclosporine is completely blunted by endothelin-1 receptor blockade.⁵ Furthermore, inhibition of superoxide anion production abolished endothelin-induced contraction of isolated vascular rings treated with cyclosporine,⁶ suggesting that superoxide anion may play a role in mediating endothelin-induced vasoconstriction. Although these studies support the notion that the hypertensive actions of endothelin may involve the formation of oxygen radicals, the importance of reactive oxygen species in mediating the chronic hypertension and renal vasoconstriction induced by endothelin in vivo is still unknown. Thus, the purpose of this study was to determine whether endothelin-induced hypertension and changes in renal hemodynamics is mediated by increased production of reactive oxygen species.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
All studies were done in 225 to 250 g male Sprague-Dawley rats purchased from Harlan Sprague-Dawley Inc. Animals were housed 3 to a cage in a temperature-controlled room (23°C) with a 12:12-hour light/dark cycle. All experimental procedures executed in this study were in accordance with National Institutes of Health Guidelines for the Use and Care of Animals and with approval by the Animal Care and Use Committee at the University of Mississippi Medical Center.

Experimental Design
Animals were divided into 4 groups: (1) control group, (2) endothelin-treated group (5 pmol/kg per minute, Alexis), (3) tempol-treated group (30 mg/kg per day, Sigma), and (4) endothelin-1 (5 pmol/kg per minute) plus tempol (30 mg/kg per day) treated group. Drugs were chronically infused for 9 days through the jugular vein by use of a mini-osmotic pump (Alzet model 2002). Catheters (PE-60) connected to a mini-osmotic pump were inserted into the jugular veins under isoflurane anesthesia as previously described.^7,8 Animals were anesthetized with isoflurane on day 7 of the experiment for insertion of femoral arterial and venous catheters (PE-50). Bladder catheters were inserted into the bladder through a midline lower abdominal incision. Renal hemodynamics and arterial pressure were measured in conscious, chronically instrumented rats on day 9 of the protocol.

Measurement of Renal Hemodynamics and Arterial Pressure in Conscious Rats
Renal hemodynamics and arterial pressure were determined in conscious control (n=12), tempol-treated rats (n=9), endothelin-1–treated (n=9) rats, and rats treated with endothelin-1 plus tempol (n=6). Measurement of renal hemodynamics was performed in conscious rats with GFR and effective renal plasma flow (ERPF) determined by the clearance of [I¹²⁵] iothalamate and para-aminohippurate, as described previously.^7,8 MAP was monitored with a pressure transducer connected to a blood pressure monitoring system.⁸

Assessment of Oxidative Stress
Oxidative stress was determined in a separate group of animals: control group (n=7), endothelin-1–treated group (n=5), tempol-treated group (n=5), and endothelin-1 plus tempol–treated group (n=5). On day 5, rats were placed in metabolic cages, and 24-hour urine was collected on ice and centrifuged for 10 minutes at 1500g, then kept at -80°C. On the 9th day of the experiment, rats were euthanized under inhalational anesthesia. Kidneys were washed with heparinized saline, excised, placed in liquid nitrogen and kept at -80°C until assays were performed.

TBARS Assay
Lipid peroxidation within the kidney was assessed by measuring malondialdehyde, as described previously.⁹ Kidneys were homogenized in buffer containing 20 mmol/L Tris-HCl, pH 7.4, containing 5 mmol/L butylated hydroxy toluene. Samples were centrifuged at 5000g at 4°C for 20 minutes, with storage of the supernatant at -80°C. Supernatant was treated with TCA 40% molar in HCL and 0.1 mol/L thiobarbituric acid and incubated at 90°C for 30 minutes. Samples were diluted with water, and the mixtures were centrifuged at 1500g for 10 minutes. Absorbance of the supernatant was read at 525 nm. Total protein concentration was determined with the use of a Sigma protein determination kit (P5656, Sigma Chemical Co).¹⁰

Determination of Urinary 8-Isoprostane PGF_2a
8-Isoprostane PGF₂ (8-ISO PGF₂) was measured according to method previously described.¹¹ We used an enzyme immunoassay kit to measure 8-ISO PGF₂ in urine (Cayman chemical kit catalog, No.516351). Urine samples were diluted with EIA buffer supplied with the kits and assayed without purification.

Detection of Superoxide Production in Isolated Vascular Smooth Muscle Cells
The direct effect of endothelin-1 on superoxide anion production in rat vascular smooth muscle cells was also determined. A10 cells, passage 3 to 6, were seeded on glass slides, incubated for 24 hours in growth media, and then washed with PBS. These cells were derived from the thoracic aorta of DB1X embryonic rats and have many of the characteristics of vascular smooth muscle cells. Cells were incubated in serum-free DMEM and endothelin-1 (10^-9, 10^-8, 10^-7, and 10^-6 mol/L) for 24 hours. After incubation, hydroethidine (5 µmol/L) was added to the medium and incubated for 15 minutes at room temperature in the dark. Fluorescence caused by conversion of hydroethidine to ethidium was used as an index of production of superoxide anion, with a Leica TCS-SP2 laser scanning confocal microscopy used as described.¹² The average fluorescence intensities were quantified by dividing the nucleus fluorescence by its area with the use of Leica confocal software.

Statistical Analysis
All data are expressed as mean±SEM. Comparisons between groups were analyzed by means of factorial ANOVA followed by the Fisher test. A value of P<0.05 was considered statistically significant

	Results

Top Abstract Introduction Methods Results Discussion References

 
Effect of Tempol on Endothelin-Induced Hypertension in Conscious Rats
Chronic infusion of endothelin-1 at the rate of 5 pm/kg per minute for 9 days in conscious rats significantly increased MAP (141±3 mm Hg versus 125±2 mm Hg in the control group, P<0.01). Tempol completely blocked the effect of endothelin-1, as MAP in the endothelin-1 plus tempol–treated group was 127±4 mm Hg. Tempol alone has no effect on MAP in control rats, as illustrated in Figure 1.

View larger version (11K): [in this window] [in a new window]   Figure 1. Effect of endothelin-1 on MAP in control and tempol-treated rats. *P<0.01 vs control, P<0.01 vs endothelin-1.

Effect of Tempol on Endothelin-Induced Changes in Renal Hemodynamics in Conscious Rats
The renal hemodynamic changes in response to endothelin-1 and tempol are illustrated in Figure 2. Endothelin-1 significantly increased RVR, as RVR averaged 15±2.5 mm Hg/mL per minute in the endothelin-1–treated group and 10±1.3 mm Hg/mL per minute in control rats. Tempol treatment significantly decreased RVR in endothelin-1–treated rats (8.6±1 mm Hg/mL per minute). Endothelin-1 decreased ERPF by 26%, as ERPF was 6.5±0.9 mL/min in endothelin-1–treated rats versus 8.7±0.7 mL/min in control rats. Tempol virtually abolished the effect of endothelin-1 on ERPF. ERPF in endothelin plus tempol was 8.5±0.75 mL/min, as compared with 8.7±0.7 mL/min in control rats. Tempol had no effect on ERPF in control rats. Endothelin-1 also had no effect on GFR in control or tempol-treated groups, as shown in Figure 3.

View larger version (15K): [in this window] [in a new window]   Figure 2. Changes in RVR and ERPF in endothelin-1–treated and endothlein-1 plus tempol–treated rats. All data are expressed as mean±SEM. *P<0.05 vs control, P<0.01 vs endothelin-1.

View larger version (10K): [in this window] [in a new window]   Figure 3. Effect of endothelin-1 on GFR in control and tempol-treated rats. All data are expressed as mean±SEM.

Increased Renal Levels of TBARS and Urinary 8-ISO PGF₂ Excretion in Rats Chronically Treated With Endothelin-1
TBARS, within the kidney, were measured to assess lipid oxidation. TBARS levels in kidney homogenates were significantly increased in endothelin-1–treated rats (462±142 ng/µg protein) versus (48±13 ng/µg protein), as compared with control rats (P<0.01). Tempol tended to reduce TBARS level (287±52 versus 462±142 ng/µg protein) in endothelin-1–treated rats; however, statistical significance was not reached.

Urinary 8-ISO PGF₂ excretion was assayed to measure the effects of ET-1 on phospholipid oxidation. Figure 4 illustrates a significant increase in urinary 8-ISO PGF₂ excretion in endothelin-1–treated rats (11±1 ng/d), as compared with control rats (7.5±1 ng/d) (P<0.01). Tempol treatment significantly blocked the effect of endothelin-1 on urinary 8-ISO PGF₂ excretion (8.9±0.8 versus 11±1 ng/d, P<0.05). Tempol alone significantly decreased urinary 8-ISO PGF₂ (4.0±0.6 versus 7.5±1.0 ng/d) in control rats (P<0.05).

View larger version (10K): [in this window] [in a new window]   Figure 4. Urinary 8-ISO PGF2 in endothelin-1–treated and tempol plus endothelin-1–treated rats. All data are expressed as mean±SEM. *P<0.01, endothelin vs control; *P<0.05, tempol vs control; P<0.05 vs endothelin-1.

Direct Effect of Endothelin-1 on Superoxide Production in Cultured Rat Vascular Smooth Muscle Cells
As shown in Figure 5, endothelin-1 caused a significant (P<0.01) and dose-dependent increase in fluorescence (E_max=52±3.5, 55.6±4, and 98±4 for 10^-8, 10^-7, and 10^-6 mol/L, respectively, versus 38.5±2.6 relative fluorescence arbitrary units in control cells that received no treatment).

View larger version (10K): [in this window] [in a new window]   Figure 5. Effect of endothelin-1 on superoxide production in vascular smooth muscle cells. All data are expressed as mean±SEM. *P<0.01 vs control, P<0.01 vs endothelin-1, 10-7 mol/L.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
A role of endothelin in mediating the renal and cardiovascular alterations in various forms of hypertension has accumulated over past decade.¹³ Results from recent in vitro studies have suggested that endothelin-l may also be an important regulator of superoxide anion formation in vascular tissue.^5,6 Administration of BQ123, a selective ET_A receptor antagonist, prevented stimulation of superoxide anion formation induced by cyclosporine and oxidized LDL.⁵ Moreover, exogenously applied endothelin-1 dose-dependently stimulated superoxide anion formation in rat aortic rings.⁶ Collectively, these studies support the notion that the renal and hypertensive actions of endothelin may involve the formation of oxygen radicals.

To determine whether endothelin-induced hypertension and changes in renal hemodynamics are mediated by increased reactive oxygen species production, we assessed the formation of reactive oxygen species in response to long-term infusion of endothelin-1 for 9 days in conscious, chronically instrumented rats. We found that endothelin-induced hypertension in rats was associated with significant increases in the urinary excretion of 8-ISO PG F₂, which is one of the stable byproducts of phospholipid oxidation. Moreover, lipid peroxides, measured as TBARS in kidney tissues, were markedly elevated (>9-fold) in rats chronically treated with endothelin. 8-ISO PG F₂ and TBARS are also elevated in other forms of hypertension such as angiotensin II–induced hypertension, renovascular, obesity, and pregnancy-induced hypertension.^9–13 Interestingly, we and others have recently reported these forms of hypertension are also associated with an increase in the endogenous formation of endothelin.^14–20 The importance of endogenous endothelin in mediating enhanced oxidative stress in various animal models of hypertension remains to be determined.

To determine the importance of reactive oxygen species in mediating the chronic hypertension induced by endothelin, we examined the effects of tempol, a stable, membrane-permeable superoxide dismutase (SOD) mimetic, in rats with endothelin-induced hypertension. Chronic infusion of endothelin-1 over 9 days increased blood pressure by 18 to 20 mm Hg. In sharp contrast, the hypertensive response to endothelin was completely abolished in rats treated with tempol. It is unlikely that the antihypertensive effect of tempol was a nonspecific effect, since tempol had no effect in normotensive control rats. Moreover, the antihypertensive effects of tempol have been reported in some but not all animal models of hypertension.^11,21 We also believe the effects of tempol in our study were through inhibition of oxidative stress, since our biomarkers of reactive oxygen species, 8-ISO PG F^2a, was significantly reduced and TBARS were attenuated by tempol treatment in rats with endothelin-induced hypertension.

We previously reported that endothelin-induced hypertension is associated with an increase in RVR and reduced pressure natriuresis.³ Endothelin also decreased renal plasma flow through vasoconstriction of the glomerular afferent and efferent arterioles.⁴ Since chronic endothelin-induced renal vasoconstriction may be mediated by the production of superoxide, we were also interested in whether tempol improves renal function. In the present study, we found that endothelin-1 significantly increased RVR. As mentioned earlier, these changes in renal hemodynamics were associated with a marked increase in lipid peroxidation within the kidney. Tempol administration significantly decreased the RVR response to endothelin. Thus, it appears that the chronic renal vasoconstriction in response to endothelin may in part be mediated through the production of reactive oxygen species.

The effect of endothelin to stimulate reactive oxygen species production may be due to direct and indirect mechanisms. Although the elevation in arterial pressure and subsequent endothelial dysfunction may be a stimulus for endothelin-induced superoxide anion formation, several studies have shown that the production of reactive oxygen species is not elevated in certain rat models of experimental hypertension such as norepinephrine-induced hypertension. To assess the direct actions of endothelin on superoxide anion production, we performed an additional in vitro study to examine the direct effects of endothelin-1 in rat vascular smooth muscle cells. Using fluorescence resulting from conversion of hydroethidine to ethidium as an indicator of superoxide anion production, we found that endothelin-1 produced a dose-dependent and significant increase in superoxide anion production in rat vascular smooth muscle cells. These findings are consistent with growing evidence for a direct effect of endothelin to stimulate reactive oxygen species production.¹²

We did not examine the potential mechanism whereby endothelin-1 stimulates superoxide anion formation or the cellular origin of superoxide anion produced by endothelin-1. It is well known that endothelial and/or smooth muscle cell NAD(P)H oxidase is an important superoxide anion–generating system.²² Recent studies have also indicated that rat smooth muscle production of superoxide anion involves a protein kinase C (PKC)-dependent pathway.²³ Since endothelin-1 is a potent stimulator of PKC in vascular smooth muscle cell, it is possible that PKC-mediated stimulation of NAD(P)H oxidase is responsible for endothelin-1–induced superoxide anion production. Further studies are necessary to examine the potential mechanism whereby endothelin causes oxidative stress.

Perspectives
We report that chronic endothelin-1–induced hypertension in rats is associated with decreases in RPF and increases in RVR and increases in TBARS and urinary 8-ISO PG F₂ excretion, markers of oxidative stress. The increase in MAP in response to endothelin-1 was completely abolished by tempol, a SOD mimetic. Tempol also markedly attenuated the RPF response to endothelin-1 and significantly decreased the RVR response to endothelin-1. Tempol also significantly decreased the level of 8-ISO PGF₂ in the endothelin-1–treated rats. Conversely, tempol had no effect on MAP or renal hemodynamics in control rats. These data indicate that formation of reactive oxygen species may play an important role in mediating the changes in renal function and hypertension induced by chronic elevations in endothelin.

	Acknowledgments

 
This work was supported by National Institutes of Health grants HL51971 and HL33947.

Received May 12, 2003; first decision June 5, 2003; accepted June 19, 2003.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Rubany GM, Polokoff MA. Endothelin: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev. 1994; 46: 325–415.[Medline] [Order article via Infotrieve]
2. Mortensen LH, Pawloski CM, Kanagy NL, Fink GD. Chronic hypertension produced by infusion of endothelin in rats. Hypertension. 1990; 15: 729–733.[Abstract/Free Full Text]
3. Wilkins FC Jr, Alberola A, Mizelle HL, Opgenorth TJ, Granger JP. Systemic hemodynamics and renal function during long-term pathophysiological increases in circulating endothelin. Am J Physiol. 1995; 268: 375–381.
4. Badr KF, Murray JJ, Breyer MD, Takahashi K, Inagami T, Harris RC. Mesangial cell, glomerular and renal vascular responses to endothelin in the rat kidney: elucidation of signal transduction pathways. J Clin Invest. 1989; 83: 336–334.[Medline] [Order article via Infotrieve]
5. Galle J, Lehmann-Bodem C, Hubner U, Heinloth A, Wanner C. CyA and OxLDL cause endothelial dysfunction in isolated arteries through endothelin-mediated stimulation of O₂^- formation. Nephrol Dial Transplant. 2000; 15: 339–346.[Abstract/Free Full Text]
6. Diederich D, Skopec J, Diederich A, Dai FX. Cyclosporine produces endothelial dysfunction by increased production of superoxide. Hypertension. 1994; 23: 957–961.[Abstract/Free Full Text]
7. Kassab S, Miller MT, Hester R, Novak J, Granger JP. Systemic hemodynamics and regional blood flow during chronic nitric oxide synthesis inhibition in pregnant rats. Hypertension. 1998; 31: 315–320.[Abstract/Free Full Text]
8. Alexander BT, Miller MT, Kassab S, Novak J, Reckelhoff JF, Kruckeberg WC, Granger JP. Differential expression of renal nitric oxide synthase isoforms during pregnancy in rats. Hypertension. 1999; 33: 435–439.[Abstract/Free Full Text]
9. Dobrian AD, Davies MJ, Schriver SD, Lauterio TJ, Prewitt RL. Oxidative stress in a rat model of obesity-induced hypertension. Hypertension. 2001; 37: 554–560.[Abstract/Free Full Text]
10. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurements with the folin phenol reagent. J Biol Chem. 1951; 193: 265–275.[Free Full Text]
11. Schnackenberg CG, Wilcox CS. Two-week administration of tempol attenuates both hypertension and renal excretion of 8-Iso prostaglandin F2 alpha. Hypertension. 1999; 33: 424–428.[Abstract/Free Full Text]
12. Wedgwood S, Dettman R W, Black SM. ET-1 stimulates pulmonary arterial smooth muscle cell proliferation via induction of reactive oxygen species. Am J Physiol Lung Cell Mol Physiol. 2001; 281: 1058–1067.
13. Schiffrin E. Role of endothelin-1 in hypertension and vascular disease. Am J Hypertens. 2001; 14: 83S–89S.[CrossRef][Medline] [Order article via Infotrieve]
14. Lerman LO, Nath KA, Rodriguez-Porcel M, Krier JD, Schwartz RS, Napoli C, Romero JC. Increased oxidative stress in experimental renovascular hypertension. Hypertension. 2001; 37: 541–546.[Abstract/Free Full Text]
15. Haas JA, Krier JD, Bolterman RJ, Juncos LA, Romero JC. Low-dose angiotensin II increases free isoprostane levels in plasma. Hypertension. 1999; 34: 983–986.[Abstract/Free Full Text]
16. Kato T, Kassab S, Wilkins FC, Kirchner K, Keiser J, Granger JP. Endothelin antagonist improve renal function in spontaneously hypertensive rats. Hypertension. 1995; 25: 883–887.[Abstract/Free Full Text]
17. Kassab S, Novak J, Miller T, Kirchner KA, Granger JP. Cardiovascular and renal actions of endothelin receptor antagonism in Dahl salt-sensitive hypertension. Hypertension. 1997; 30: 682–686.[Abstract/Free Full Text]
18. Alexander BT, Cockrell KL, Herrington JN, Granger JP. Enhanced renal expression of preproendothelin mRNA during chronic angiotensin II hypertension. Am J Physiol. 2001; 280: R1388–R1392.
19. Alexander BT, Rinewalt AN, Cockrell KL, Bennett WA, Granger JP. Endothelin-A receptor blockade attenuates the hypertension in response to chronic reductions in uterine perfusion pressure. Hypertension. 2001; 37: 485–489.[Abstract/Free Full Text]
20. Granger JP, Alexander BT, Bennett WA, Khalil RA. Pathophysiology of pregnancy-induced hypertension. Am J Hypertens. 2001; 14: S178–S185.[CrossRef][Medline] [Order article via Infotrieve]
21. Harrison DG. Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest. 1997; 100: 2153–2157.[Medline] [Order article via Infotrieve]
22. Fukui T, Ishizaka N, Rajagopalan S, Laursen JB, Capers Q, Taylor WR, Harrison DG, Hector de Leon , Wilcox JN, Griendling KK. p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats. Circ Res. 1997; 80: 45–51.[Abstract/Free Full Text]
23. Heitzer T, Wenzel U, Hink U, Krollner D, Skatchkov M, Stahl RA, MacHarzina R, Brasen JH, Meinertz T, Munzel T. Increased NAD(P)H oxidase-mediated superoxide production in renovascular hypertension: evidence for an involvement of protein kinase C. Kidney Int. 1999; 55: 252–260.[CrossRef][Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				S. Cottone, G. Mule, M. Guarneri, A. Palermo, M. C. Lorito, R. Riccobene, R. Arsena, F. Vaccaro, A. Vadala, E. Nardi, et al. Endothelin-1 and F2-isoprostane relate to and predict renal dysfunction in hypertensive patients Nephrol. Dial. Transplant., September 4, 2008; (2008) gfn489v1. [Abstract] [Full Text] [PDF]

				E. C. Viel, K. Benkirane, D. Javeshghani, R. M. Touyz, and E. L. Schiffrin Xanthine oxidase and mitochondria contribute to vascular superoxide anion generation in DOCA-salt hypertensive rats Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H281 - H288. [Abstract] [Full Text] [PDF]

				A. Just, C. L. Whitten, and W. J. Arendshorst Reactive oxygen species participate in acute renal vasoconstrictor responses induced by ETA and ETB receptors Am J Physiol Renal Physiol, April 1, 2008; 294(4): F719 - F728. [Abstract] [Full Text] [PDF]

				C. M. Troncoso Brindeiro, A. Q. da Silva, K. J. Allahdadi, V. Youngblood, and N. L. Kanagy Reactive oxygen species contribute to sleep apnea-induced hypertension in rats Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2971 - H2976. [Abstract] [Full Text] [PDF]

				G. T. C. Wong and M. G. Irwin Contrast-induced nephropathy Br. J. Anaesth., October 1, 2007; 99(4): 474 - 483. [Abstract] [Full Text] [PDF]

				J. M. Sasser, J. C. Sullivan, J. L. Hobbs, T. Yamamoto, D. M. Pollock, P. K. Carmines, and J. S. Pollock Endothelin A Receptor Blockade Reduces Diabetic Renal Injury via an Anti-Inflammatory Mechanism J. Am. Soc. Nephrol., January 1, 2007; 18(1): 143 - 154. [Abstract] [Full Text] [PDF]

				S. K. Fellner and W. Arendshorst Endothelin-A and -B receptors, superoxide, and Ca2+ signaling in afferent arterioles Am J Physiol Renal Physiol, January 1, 2007; 292(1): F175 - F184. [Abstract] [Full Text] [PDF]

				D. Wang, P. Jose, and C. S. Wilcox beta1 Receptors Protect the Renal Afferent Arteriole of Angiotensin-Infused Rabbits from Norepinephrine-Induced Oxidative Stress J. Am. Soc. Nephrol., December 1, 2006; 17(12): 3347 - 3354. [Abstract] [Full Text] [PDF]

				A. J. Bagnall, N. F. Kelland, F. Gulliver-Sloan, A. P. Davenport, G. A. Gray, M. Yanagisawa, D. J. Webb, and Y. V. Kotelevtsev Deletion of Endothelial Cell Endothelin B Receptors Does Not Affect Blood Pressure or Sensitivity to Salt Hypertension, August 1, 2006; 48(2): 286 - 293. [Abstract] [Full Text] [PDF]

				J. C. Sullivan, J. S. Pollock, and D. M. Pollock Superoxide-dependent hypertension in male and female endothelin B receptor-deficient rats. Experimental Biology and Medicine, June 1, 2006; 231(6): 818 - 823. [Abstract] [Full Text] [PDF]

				X. Dai, X. Cao, and D. L. Kreulen Superoxide anion is elevated in sympathetic neurons in DOCA-salt hypertension via activation of NADPH oxidase Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1019 - H1026. [Abstract] [Full Text] [PDF]

				Y. E. Lau, J. J. Galligan, D. L. Kreulen, and G. D. Fink Activation of ETB receptors increases superoxide levels in sympathetic ganglia in vivo Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R90 - R95. [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]

				E. D. Loomis, J. C. Sullivan, D. A. Osmond, D. M. Pollock, and J. S. Pollock Endothelin Mediates Superoxide Production and Vasoconstriction through Activation of NADPH Oxidase and Uncoupled Nitric-Oxide Synthase in the Rat Aorta J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1058 - 1064. [Abstract] [Full Text] [PDF]

				A. Svatikova, R. Wolk, L. O. Lerman, L. A. Juncos, E. L. Greene, J. P. McConnell, and V. K. Somers Oxidative stress in obstructive sleep apnoea Eur. Heart J., November 2, 2005; 26(22): 2435 - 2439. [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]

				Y. Ge, P. K. Stricklett, A. K. Hughes, M. Yanagisawa, and D. E. Kohan Collecting duct-specific knockout of the endothelin A receptor alters renal vasopressin responsiveness, but not sodium excretion or blood pressure Am J Physiol Renal Physiol, October 1, 2005; 289(4): F692 - F698. [Abstract] [Full Text] [PDF]

				K. Thakali, S. L. Demel, G. D. Fink, and S. W. Watts Endothelin-1-induced contraction in veins is independent of hydrogen peroxide Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1115 - H1122. [Abstract] [Full Text] [PDF]

				J. Li, Y.-J. Chen, and J. Quilley Effect of Tempol on Renal Cyclooxygenase Expression and Activity in Experimental Diabetes in the Rat J. Pharmacol. Exp. Ther., August 1, 2005; 314(2): 818 - 824. [Abstract] [Full Text] [PDF]

				D. M. Pollock Endothelin, Angiotensin, and Oxidative Stress in Hypertension Hypertension, April 1, 2005; 45(4): 477 - 480. [Full Text] [PDF]

				S. K. Fellner and L. Parker Endothelin-1, superoxide and adeninediphosphate ribose cyclase in shark vascular smooth muscle J. Exp. Biol., March 15, 2005; 208(6): 1045 - 1052. [Abstract] [Full Text] [PDF]

				A. A. Elmarakby, E. D. Loomis, J. S. Pollock, and D. M. Pollock NADPH Oxidase Inhibition Attenuates Oxidative Stress but Not Hypertension Produced by Chronic ET-1 Hypertension, February 1, 2005; 45(2): 283 - 287. [Abstract] [Full Text] [PDF]

				I. N. Bratz and N. L. Kanagy Nitric oxide synthase-inhibition hypertension is associated with altered endothelial cyclooxygenase function Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2394 - H2401. [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]

				F. Amiri, A. Virdis, M. F. Neves, M. Iglarz, N. G. Seidah, R. M. Touyz, T. L. Reudelhuber, and E. L. Schiffrin Endothelium-Restricted Overexpression of Human Endothelin-1 Causes Vascular Remodeling and Endothelial Dysfunction Circulation, October 12, 2004; 110(15): 2233 - 2240. [Abstract] [Full Text] [PDF]

				X. Dai, J. J. Galligan, S. W. Watts, G. D. Fink, and D. L. Kreulen Increased O2{middle dot}- Production and Upregulation of ETB Receptors by Sympathetic Neurons in DOCA-Salt Hypertensive Rats Hypertension, May 1, 2004; 43(5): 1048 - 1054. [Abstract] [Full Text] [PDF]

				H. Xu, G. D. Fink, and J. J. Galligan Tempol Lowers Blood Pressure and Sympathetic Nerve Activity But Not Vascular O2- in DOCA-Salt Rats Hypertension, February 1, 2004; 43(2): 329 - 334. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 42/4/806    most recent 01.HYP.0000084372.91932.BAv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services