Published online before print June 2, 2003, doi: 10.1161/01.HYP.0000078357.92682.EC
(Hypertension. 2003;42:49.)
© 2003 American Heart Association, Inc.
Scientific Contribution |
Endothelin Antagonism on Aldosterone-Induced Oxidative Stress and Vascular Remodeling
From the Canadian Institutes of Health Research (CIHR) Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal (IRCM), University of Montreal, Montreal, Quebec, Canada.
Correspondence to Ernesto L. Schiffrin, MD, PhD, FRCPC, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7. E-mail schiffe{at}ircm.qc.ca
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Endothelin A (ETA) receptor blockade has prevented vascular remodeling in aldosterone and salt-induced hypertension. To evaluate effects of the ETA receptor antagonist, BMS 182874, compared with the aldosterone antagonist, spironolactone, on vascular remodeling in aldosterone-infused rats not exposed to a high salt diet, Sprague-Dawley rats were infused subcutaneously with aldosterone (0.75 µg/h) and treated with BMS 182874 (40 mg · kg-1 · d-1), spironolactone, or hydralazine (both 25 mg · kg-1 · d-1) while receiving a normal salt diet for 6 weeks. Aldosterone increased systolic BP (P<0.01), plasma endothelin (3.33±0.32 versus 1.85±0.40 pmol/L in control, P<0.05), systemic oxidative stress as shown by plasma thiobarbituric acid–reacting substances and vascular nicotinamide adenine dinucleotide phosphate (NADPH) activity. Aldosterone increased small artery media thickness (17.7±0.9 versus 13.6±0.8 µm in control, P<0.05) and media/lumen ratio (7.6±0.4 versus 5.5±0.4% in control, P<0.05), with growth index of 21% indicating hypertrophic remodeling. Laser confocal microscopy showed increased collagen and fibronectin deposition and intercellular adhesion molecule-1 (ICAM-1) content in the vessel wall of aldosterone-infused rats. The 3 treatments lowered BP, although hydralazine was slightly less effective. BMS 182874 and spironolactone decreased oxidative stress, normalized the hypertrophic remodeling, decreased collagen and fibronectin deposition, and reduced ICAM-1 abundance in the vascular wall of aldosterone-infused rats, whereas hydralazine only reduced NADPH activity in aorta but did not affect the remaining parameters. Vascular remodeling of small arteries occurs in aldosterone-infused rats exposed to a normal salt diet and may be mediated in part by ET-1 via stimulation of ETA receptors. Endothelin blockade may exert beneficial effects on vascular remodeling, fibrosis, oxidative stress, and adhesion molecule expression in aldosterone-induced hypertension.
Key Words: mineralocorticoids • receptors, endothelin • arteries • resistance • extracellular matrix • free radicals
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Aldosterone, which is involved in the regulation of body sodium and water homeostasis, has also been shown to induce cardiac remodeling and fibrosis,1,2 vascular hypertrophy,3–5 and impaired endothelial function.6 Endothelin-1 (ET-1), a potent vasoconstrictor peptide produced in the vessel wall among other tissues, mainly by vascular endothelial cells,7 plays a central role in vascular remodeling in some forms of experimental and, perhaps, human hypertension.8 Activation of vascular ET-1 production is associated with hypertrophic remodeling of resistance arteries.9,10 The local production of ET-1 may induce inflammation,11–12 which is increasingly recognized as participating in the pathogenesis of cardiovascular disease. There are several known relationships between aldosterone and ET-1. Patients with primary aldosteronism have increased circulating ET levels.13 ET-1 inhibits basal or stimulated renin synthesis in vitro and in vivo14,15 and stimulates aldosterone secretion.16,17 The effect of aldosterone on rats may depend on salt status.1 ETA receptor blockade prevents vascular remodeling in aldosterone and salt-induced hypertension.5 Furthermore, oxidative stress may increase ET-1 synthesis in endothelial and human vascular smooth muscle cells (VSMCs),18 and aldosterone may activate production of reactive oxygen species.6
The aim of this study was to examine remodeling of resistance arteries in aldosterone-infused rats in the absence of salt loading and mechanisms involved therein. We hypothesized that these aldosterone-induced effects are mediated through ET-1–sensitive pathways that involve oxidative stress. The latter may contribute to vascular remodeling, fibrosis, and inflammation, even if rats are not challenged with a high salt diet. We also compared the effect of blockade of ETA receptors with the effect of the mineralocorticoid receptor antagonist spironolactone and, to account for BP lowering, tested a vasodilator, hydralazine.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animal Experiments
The study protocol was approved by the Clinical Research Institute Animal Care Committee and conducted according to recommendations of the Canadian Council of Animal Care. Rats were housed under conditions of constant humidity (60%) and temperature (22°C) and exposed to 12-hour light/dark cycles. Forty male Sprague-Dawley rats (8 rats per group; Charles River, St Constant, Québec, Canada) weighing 200 g each were studied. Model 2002 mini-osmotic pumps (Alza Corporation), infusing 0.5 µL/h for 2 weeks, were implanted subcutaneously under anesthesia, with 50 mg/kg ketamine and 5 mg/kg xylazine given intramuscularly, and replaced every 2 weeks. The pumps infused vehicle or 0.75 µg/h d-aldosterone (Sigma Chemical Company) dissolved in 0.9% saline. BMS 182874, a highly selective ETA receptor antagonist19 (obtained from Dr James Powell, Bristol-Myers Squibb, Princeton, NJ) (40 mg · kg-1 · d-1), spironolactone (25 mg · kg-1 · d-1), and hydralazine (25 mg · kg-1 · d-1), which in previous experiments induced a similar degree of BP lowering, were given with food for 6 weeks starting at the time of aldosterone infusion. Systolic BP was measured by the tail-cuff method.
Preparation and Study of Small Arteries
Rats were killed by decapitation after 6 weeks of aldosterone infusion. A third-order branch of the mesenteric vasculature was isolated and mounted on a pressurized myograph as described previously.20 Endothelium-dependent and -independent relaxation were assessed in norepinephrine (10-5 mol/L)-precontracted resistance arteries with acetylcholine and sodium nitroprusside, respectively. Lumen and media dimensions were measured with intraluminal pressure maintained at 45 mm Hg after being deactivated with 10 mmol/L EGTA.20
NADPH Oxidase Activity
Activity of NADPH oxidase was measured in aortic segments and mesenteric arteries by lucigenin chemiluminescence (5 µmol/L)21, using NADPH (100 µmol/L) as substrate. Luminescence was measured every 1.8 seconds for 3 minutes in a luminometer (AutoLumat LB 953, Berthold). Background NADPH oxidase activity was measured at the beginning of each experiment. Activity of NADPH oxidase, after adding NADPH as substrate, was calculated by subtracting background activity. Specificity of the lucigenin signal for ·O2- generation was tested by adding diphenylene iodinium, a flavoprotein inhibitor, and tempol, a superoxide dismutase mimetic, which abolished the NADPH-induced response. Basal superoxide production without NADPH was barely detectable.
Laser Confocal Immunofluorescence Microscopy of Mesenteric Arteries
Vessels were fixed for laser confocal microscopy as previously described.22 Briefly, arteries were incubated with anti-collagen type I/III antibody (1:20, Calbiochem) and anti-fibronectin antibody (1:20, Calbiochem), and anti-intracellular adhesion molecule-1 (ICAM-1) antibody (mouse monoclonal IgG2a, 1:50, Santa Cruz Biotechnology, Inc) for 16 hours at 4°C. The vessel was washed and incubated for 1 hour at room temperature with fluorescein-conjugated F (ab')2 fragments of anti-mouse IgG (20 µg/mL), anti-rabbit IgG (40 µg/mL) (both from Chemicon International), and 200 µg/mL Alexa Fluor 647® anti-mouse IgG (Molecular Probes, Inc) for 1 hour at room temperature, respectively. Rhodamine phalloidin (10 µmol/L, Sigma) was added for the final 30 minutes of incubation to stain 
-actin. After rinsing, the artery was mounted in 1:1 glycerol/PBS (pH 7.4) on a glass coverslip and studied with a laser scanning microscope (LSM) 510 system (Zeiss). An argon laser (488 nm) and two helium neon lasers (543 nm and 633 nm) were used with the following settings: stack size 1024x1024 pixels, pixel time 2.24 µs. Fluorescein isothiocyanate (FITC) was excited at 488 nm and captured as green; rhodamine, at 543 nm and captured as red; and Alexa Fluor 647, at 633 nm and captured as green after color-code transformation. The specimen was scanned in a point-by-point, line-by-line system. Using the Z-sectioning optical device, we obtained a stack of slice images (25 to 30 sections of 1.5- to 2.5-µm slices). In negative control samples without adding the first antibody, there was little or no autofluorescence on the vessel. Collagen and fibronectin in the vascular media were quantified by imaging (Northern Eclipse program, EMPIX Imaging Inc).
Measurement of Immunoreactive ET in Plasma
Plasma immunoreactive ET was measured by radioimmunoassay after passage though a C18 Sep-Pak cartridge as previously described.23 Intra-assay and interassay variation was below 15%.
Measurement of Thiobarbituric Acid–Reacting Substances in Plasma
Blood collected on EDTA was centrifuged and the plasma stored at -20°C overnight. Plasma thiobarbituric acid–reacting substances (TBARs) were measured colorimetrically.24 TBARs values were expressed in µmol/mL malondialdehyde (MDA) equivalents. Briefly, plasma was mixed with 2% butylated hydroxytoluene and quintanilla reagent (26 mmol/L thiobarbituric acid and 918 mmol/L trichloroacetic acid) and boiled for 15 minutes. The reaction mixture was cooled and centrifuged at 3000g for 10 minutes. The soluble phase was measured with a spectrophotometer at 535 nm. MDA standards (Sigma) were diluted in the range of 0 to 4 µmol/mL.
Data Analysis
Data are presented as mean±SEM. Groups were compared by ANOVA, using repeated-measurements testing and Newman-Keuls test where appropriate. P<0.05 was considered significant. Growth index was calculated as the difference between the cross-sectional area of the media from aldosterone-infused and control rats divided by that of control rats.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Systolic Blood Pressure, Heart Weight, and Plasma ET levels
Aldosterone-infused rats exhibited significantly elevated systolic BP after 1 week (Figure 1). Systolic BP was significantly lower in aldosterone-infused rats treated with BMS 182874, spironolactone, or hydralazine. The response to hydralazine however seemed slower than to the other agents, and BP was not different from that of untreated aldosterone-infused rats during the first week. After the first week, BP in the hydralazine group tended to remain higher (although not significantly different) than in response to BMS 182874 or spironolactone. Heart weight normalized for body weight was greater in aldosterone-infused rats. Spironolactone significantly decreased relative heart weight, whereas BMS182874 or hydralazine had no effect on relative heart weight (Table). There was no significant difference in body weight between groups. Plasma endothelin was increased in aldosterone-infused rats compared with control rats. Spironolactone tended to reduce plasma endothelin levels without achieving statistical significance. Neither BMS nor hydralazine altered plasma endothelin (Table).
|
P<0.01 vs aldosterone-infused rats.
|
Measurement of Oxidative Stress: Vascular NADPH Oxidase Activity and Plasma TBARs (MDA)
NADPH oxidase activity, a major source of superoxide anion in the vasculature, was significantly (P<0.01) increased in mesenteric arteries and aorta of aldosterone-infused rats compared with controls (Figures 2A and 2B). BMS 182874 and spironolactone decreased NADPH oxidase activity in mesenteric arteries and aorta. Hydralazine decreased the NADPH oxidase activity only in aorta but not in mesenteric arteries.
|
Plasma TBARs (measured as MDA) levels were significantly higher (P<0.01) in aldosterone-infused rats compared with controls. BMS 182874 or spironolactone significantly decreased (P<0.01) plasma MDA (Figure 2C), whereas hydralazine had no effect.
Endothelial Function of Mesenteric Resistance Arteries
Mesenteric small artery relaxation in response to acetylcholine and to sodium nitroprusside (SNP) was unchanged after aldosterone infusion in this particular set of experiments. Neither BMS 182874 nor spironolactone or hydralazine had any effect on endothelium-dependent or -independent relaxation (data not shown).
Morphological Characteristics of Resistance Arteries
Aldosterone infusion resulted in increased media thickness and media-to-lumen ratio (Figures 3B and 3C) (P<0.05) and a trend to an increase in media cross-sectional area of mesenteric arteries (P<0.04 only on a one-sided post hoc t test) compared with control rats (Figure 3D). The growth index of small arteries from aldosterone-infused rats was 21%, indicating moderate hypertrophic remodeling. BMS 182874 or spironolactone treatment prevented hypertrophic remodeling induced by aldosterone (P<0.05 for media width and media-to-lumen ratio; only on one-sided post hoc t test for media cross section after BMS 182874, P<0.02, or spironolactone, P<0.03), whereas hydralazine had no effect on the structure of small arteries despite its hypotensive action.
|
Vascular Extracellular Matrix Deposition and Inflammatory Markers
Aldosterone infusion increased collagen and fibronectin deposition as well as density in the media of mesenteric arteries compared with control rats (Figures 4 and 5
), which was prevented by either BMS 182874 or spironolactone. ICAM-1 expression was increased in the endothelial cell layer and adventitia of small arteries in aldosterone-infused rats (Figure 6). The increase of ICAM-1 was prevented by BMS 182874 and by spironolactone, but hydralazine had no effect on either vascular extracellular matrix or inflammatory mediators.
|
|
P<0.01 vs aldosterone-infused rats.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Aldosterone infusion raised systolic BP, increased plasma ET levels, induced oxidative stress (elevated plasma TBARs and enhanced vascular NADPH oxidase activity), and resulted in hypertrophic remodeling of small arteries. Vascular changes were associated with collagen and fibronectin deposition in the media and increased abundance of ICAM-1 in the vascular wall. The 3 antihypertensive treatments used prevented the rise in systolic BP, although the response to hydralazine was delayed and seemed weaker than to the other agents. BMS 182874 and spironolactone decreased oxidative stress, normalized resistance artery growth, prevented collagen and fibronectin deposition, and decreased ICAM-1 expression in the vascular wall of aldosterone-infused rats, whereas hydralazine failed to have any major effect on any of these parameters despite lowering BP. Spironolactone tended to decrease plasma endothelin levels. The present results suggest that, even in the absence of salt loading, ET-1 acting via ETA receptors plays an important role in small artery remodeling in response to aldosterone, an effect mediated in part via oxidative stress.
Administration of deoxycorticosterone and salt to unilaterally nephrectomized rats is associated with severe BP elevation and activation of the vascular,25 cardiac,26 and renal endothelin systems.27 If no salt was administered and blood pressure rose less, the endothelin system was not activated and vascular remodeling was less pronounced.28 Administration of aldosterone plus salt upregulated vascular5 and cardiac ET-1.29 Salt thus appears to play an important role in blood pressure elevation, activation of the endothelin system, and vascular damage. In the present study, plasma immunoreactive endothelin rose significantly. Although not a reliable indicator of tissue levels of ET-1, this argues in favor of activation of tissue ET-1 production even in the presence of moderate BP rise and no salt loading.
Mechanisms whereby aldosterone infusion results in increased tissue production of ET-1 remain unclear. We previously showed a role for vasopressin, stimulated in the DOCA-salt hypertensive rat, partly mediating the upregulation of ET-1.30,31 Mineralocorticoid receptors have been found in endothelial and VSMCs in the aorta and pulmonary artery of rabbit and in cardiac myocytes and endothelial cells.32,33 It is possible that there is a direct effect of aldosterone on ET-1 production, but this has not yet been demonstrated.
Activity of vascular NADPH oxidase, a major source of superoxide anion in blood vessels,34 was increased, associated with increased lipid peroxidation measured by TBARs in plasma, suggesting enhanced production of reactive oxygen species. Oxidative stress may be involved in the upregulation of vascular ET-1 or could be a consequence of its increase. Reactive oxygen species react with nitric oxide (NO) to produce peroxynitrite (OONO-), with subsequent lipid peroxidation of arachidonic acid and formation of F2-isoprostanes. Free radical–generated F2-isoprostanes stimulate ET-1 expression on endothelial cells.35 In other studies, reactive oxygen species stimulated ET-1 generation by endothelial cells.19 In the present experiments, the ETA antagonist decreased oxidative stress, which may mean that ET-1 stimulated free radical production. Because BP elevation is accompanied by increased oxidative stress,36,37 this response to ETA antagonism could be related to BP lowering. Hydralazine administration, which lowered BP and may inhibit NADPH oxidase,38 only partially reduced enhanced NADPH oxidase activity in aorta without effect on mesenteric arteries and did not significantly reduce plasma TBARs. However, it must be acknowledged that, in this particular set of experiments, hydralazine seemed slightly less effective than the other agents, as already mentioned. Nevertheless, we believe that, taken together, these data suggest that BP lowering did not reduce oxidative stress and that ET-1 may have stimulated reactive oxygen species generation. However, a role of aldosterone-induced oxidative stress on ET-1 production cannot be completely ruled out.
BMS 182874 and spironolactone had similar effects on oxidative stress. In humans blockade of mineralocorticoid receptors with spironolactone improved endothelium-dependent relaxation by increasing NO bioavailability through reduction in vascular oxidative stress.6 Together with other data, this agrees with the notion that when oxidative stress and ET-1 are elevated, bioactive NO is reduced, and conversely, when they are low, NO is normal. Nitric oxide may downregulate the expression of ET-1. However, in agreement with our previous study in aldosterone and salt-induced hypertension,5 here endothelial function of mesenteric arteries in aldosterone-infused rats was not altered, suggesting that the increased ET-1 production and enhanced oxidative stress were regulated independently from NO. A possible explanation for normal endothelial function is that BP elevation was less severe compared with DOCA-salt- or Dahl-salt–sensitive rats in which endothelial dysfunction in association with increased oxidative stress are nearly always documented.39,40
The presence of hypertrophic remodeling of small arteries in aldosterone-infused rats agrees with studies in primary aldosteronism patients,41 in whom increased media and media-to-lumen ratio of resistance arteries have been documented. Confocal microscopy showed an associated change in extracellular matrix components, consistent with enhanced collagen deposition associated with small artery remodeling in DOCA-salt–hypertensive rats.22 ET-1 activates the procollagen I promoter42 in renal vessels and glomeruli. The ETA antagonist results suggest that increased collagen and fibronectin in response to aldosterone was mediated via ET-1 and activation of ETA receptors.
Inflammation plays an important role in atherosclerosis, hypertension, and diabetes.43 In humans, this notion has been based primarily on the demonstration of elevated levels of serum C-reactive protein. Here, associated with vascular remodeling and fibrosis, there was increased expression of ICAM-1, which is known to participate in the inflammatory process. These results demonstrate for the first time that, in this model of hypertension, an inflammatory response is associated with vascular remodeling and enhanced oxidative stress. Adhesion molecules participate in recruitment of circulating leukocytes to sites of inflammation and may be activated by nuclear factor-
B (NF-B) and activator protein-1 (AP-1) during the inflammatory response.44 NF-B activation may result from increased oxidative stress, which may be induced by ET-1.45
There are conflicting reports on the effects of endothelin antagonists in experimental hypertension. In mineralocorticoid or salt-induced hypertensive models in which preproET-1 overexpression has been demonstrated in blood vessels, endothelin receptor antagonists decreased blood pressure and improved vascular remodeling beyond blood pressure lowering.5,9 In contrast, the spontaneously hypertensive rat (SHR)46 and high-renin rat models of hypertension,47 including transgenic (mREN2)27 rats,48,49,50 a model of monogenic renin-dependent hypertension, are characterized by absence of vascular preproET-1 overexpression, and endothelin receptor antagonists have no effect on left ventricular hypertrophy or vascular remodeling. Interestingly, in transgenic (mREN2)27 rats, aldosterone secretion was endothelin-dependent.49
In summary, an ETA receptor antagonist normalized hypertrophic vascular remodeling, oxidative stress, extracellular matrix accumulation, and adhesion molecule expression, suggesting that increased production of ET-1 acting via ETA receptors may trigger elevated oxidative stress, followed by upregulation of NF-B, adhesion molecules and chemokines, extracellular matrix accumulation (collagen and fibronectin deposition), and vascular growth. We believe that BP did not appear to have a role in the prevention of remodeling, fibrosis, oxidative stress, and adhesion molecule expression, because hydralazine was without effect despite its hypotensive action. A limitation of the study is that hydralazine was slightly less effective in this experimental paradigm than the other agents, not allowing us to rule out totally a role of BP.
Perspectives
Blockade of the endothelin system may exert beneficial effects on vascular remodeling in aldosterone-induced hypertension, and blockade of aldosterone effects may in part abrogate the pathophysiological participation of the endothelin system in cardiovascular disease.
|
Acknowledgments |
|---|
This work was supported by grant 37917 to E.L.S. and a group grant to the Multidisciplinary Research Group on Hypertension at IRCM, both from the Canadian Institute of Health Research (CIHR). Dr Pu was supported by a fellowship from the Heart and Stroke Scientific Research Corporation of Canada. The authors are grateful to Suzanne Diébold and André Turgeon for their excellent technical assistance.
Received March 11, 2003; first decision March 26, 2003; accepted May 8, 2003.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Brilla CG, Weber KT. Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med. 1992; 120: 893–901.[Medline] [Order article via Infotrieve]
- Rossi GP, Di Bello V, Ganzaroli C, Sacchetto A, Cesari M, Bertini A, Giorgi D, Scognamiglio R, Mariani M, Pessina AC. Excess aldosterone is associated with alterations of myocardial texture in primary aldosteronism. Hypertension. 2002; 40: 23–27.
[Abstract/Free Full Text] - Rocha R, Chander PN, Khanna K, Zuckerman A, Stier CT Jr. Mineralocorticoid blockade reduces vascular injury in stroke prone hypertensive rats. Hypertension. 1998; 31: 451–458.
[Abstract/Free Full Text] - Rocha R, Chander PN, Zuckerman A, Stier CT Jr. Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats. Hypertension. 1999; 33: 232–237.
[Abstract/Free Full Text] - Park JB, Schiffrin EL. ET(A) receptor antagonist prevents blood pressure elevation and vascular remodeling in aldosterone-infused rats. Hypertension. 2001; 37: 1444–1449.
[Abstract/Free Full Text] - Farquharson CA, Struthers AD. Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation. 2000; 101: 594–597.
[Abstract/Free Full Text] - Yanagisawa M, Kurihara H, Kumura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988; 332: 411–415.[CrossRef][Medline] [Order article via Infotrieve]
- Schiffrin EL. Role of endothelin-1 in hypertension. Hypertension. 1999; 34: 876–881.
[Abstract/Free Full Text] - Li J-S, Larivière R, Schiffrin EL. Effect of a nonselective endothelin antagonist on vascular remodeling in DOCA-salt hypertensive rats: evidence for a role of endothelin in vascular hypertrophy. Hypertension. 1994; 24: 183–188.
[Abstract/Free Full Text] - Schiffrin EL, Larivière R, Li JS, Sventek P, Touyz RM. Deoxycorticosterone acetate plus salt induces overexpression of vascular endothelin-1 and severe vascular hypertrophy in spontaneously hypertensive rats. Hypertension. 1995; 25: 769–773.
[Abstract/Free Full Text] - Cambiaggi C, Mencarelli M, Muscettola M, Grasso G. Gene expression of endothelin-1 (ET-1) and release of mature peptide by activated human neutrophils. Cytokine. 2001; 14: 230–233.[CrossRef][Medline] [Order article via Infotrieve]
- Tostes R, Touyz RM, He G, Chen X, Schiffrin EL. Contribution of ET-1 to renal AP-1 activation and macrophage infiltration in aldosterone-induced hypertension. Clin Sci. 2002; 103: 25S–30S.[Medline] [Order article via Infotrieve]
- Letizia C, De Toma G, Cerci S, Scuro L, De Ciocchis A, D’Ambrosio C, Massa R, Cavallaro A, Scavo D. Plasma endothelin-1 levels in patients with aldosterone-producing adenoma and pheochromocytoma. Clin Exp Hypertens. 1996; 18: 921–931.[CrossRef][Medline] [Order article via Infotrieve]
- Scholz H, Krämer BK, Hamann M, Götz KH, Kurtz A. Effects of endothelins on renin secretion from rat kidneys. Acta Physiol Scand. 1995; 155: 173–182.[Medline] [Order article via Infotrieve]
- Matsumura Y, Hisaki K, Ohyama T, Hayashi K, Morimoto S. Effects of endothelin on renal function and renin secretion in anesthetized rats. Eur J Pharmacol. 1989; 166: 577–580.[CrossRef][Medline] [Order article via Infotrieve]
- Cozza EN, Gomez-Sanchez CE. Mechanisms of ET-1 potentiation of angiotensin II stimulation of aldosterone production. Am J Physiol. 1993; 265: E179–E183.[Medline] [Order article via Infotrieve]
- Rossi GP, Sacchetto A, Cesari M, Pessina AC. Interactions between endothelin-1 and the renin-angiotensin-aldosterone system. Cardiovasc Res. 1999; 43: 300–307.
[Abstract/Free Full Text] - Kahler J, Mendel S, Weckmuller J, Orzechowski HD, Mittmann C, Koster R, Paul M, Meinertz T, Munzel T. Oxidative stress increases synthesis of big endothelin-1 by activation of the endothelin-1 promoter. J Mol Cell Cardiol. 2000; 32: 1429–1437.[CrossRef][Medline] [Order article via Infotrieve]
- Bradbury RH, Bath C, Butlin RJ, Dennis M, Heys C, Hunt SJ, James R, Mortlock AA, Sumner NF, Tang EK, Telford B, Whiting E, Wilson C. New non-peptide endothelin-A receptor antagonists: synthesis, biological properties, and structure-activity relationships of 5-(dimethylamino)-N-pyridyl-,-N-pyrimidinyl-,-N-pyridazinyl-, and -N-pyrazinyl-1-naphthalenesulfonamides. J Med Chem. 1997; 40: 996–1004.[CrossRef][Medline] [Order article via Infotrieve]
- Sharifi AM, Schiffrin EL. Endothelin receptors mediating vasoconstriction in rat pressurized small arteries. Can J Physiol Pharmacol. 1996; 74: 934–939.[CrossRef][Medline] [Order article via Infotrieve]
- Chen X, Touyz RM, Park JB, Schiffrin EL. Antioxidant effects of vitamins C and E are associated with altered activation of vascular NADPH oxidase and superoxide dismutase in stroke-prone SHR. Hypertension. 2001; 38: 606–611.
[Abstract/Free Full Text] - Pu Q, Touyz RM, Schiffrin EL. Comparison of angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP) and dual ACE/NEP inhibition on blood pressure and resistance arteries of deoxycorticosterone acetate-salt hypertensive rats. J Hypertens. 2002; 20: 899–907.[CrossRef][Medline] [Order article via Infotrieve]
- Schiffrin EL, Thibault G. Plasma endothelin in human essential hypertension. Am J Hypertens. 1991; 4: 303–308.[Medline] [Order article via Infotrieve]
- Schisterman EF, Faraggi D, Browne R, Freudenheim J, Dorn J, Muti P, Armstrong D, Reiser B, Trevisan M. TBARS and cardiovascular disease in a population-based sample. J Cardiovasc Risk. 2001; 8: 219–225.[CrossRef][Medline] [Order article via Infotrieve]
- Larivière R, Thibault G, Schiffrin EL. Increased endothelin-1 content in blood vessels of deoxycorticosterone acetate-salt hypertensive but not in spontaneously hypertensive rats. Hypertension. 1993; 21: 294–300.
[Abstract/Free Full Text] - Larivière R, Deng LY, Day R, Sventek P, Thibault G, Schiffrin EL. Increased endothelin-1 gene expression in the endothelium of coronary arteries and endocardium in the DOCA-salt hypertensive rat. J Mol Cell Cardiol. 1995; 27: 2123–2131.[CrossRef][Medline] [Order article via Infotrieve]
- Deng LY, Day R, Schiffrin EL. Localization of sites of enhanced expression of endothelin-1 in the kidney of DOCA-salt hypertensive rats. J Am Soc Nephrol. 1996; 7: 1158–1164.[Abstract]
- Schiffrin EL, Larivière R, Li JS, Sventek P. Enhanced expression of the endothelin-1 gene in blood vessels of DOCA-salt hypertensive rats: Correlation with vascular structure. J Vasc Res. 1996; 33: 235–248.[Medline] [Order article via Infotrieve]
- Park JB, Schiffrin EL. Cardiac and vascular fibrosis and hypertrophy in aldosterone-infused rats: role of endothelin-1. Am J Hypertens. 2002; 15: 164–169.[CrossRef][Medline] [Order article via Infotrieve]
- Intengan HD, He G, Schiffrin EL. Effect of V1 vasopressin antagonism on small artery structure and vascular expression of preproendothelin-1 in DOCA-salt hypertensive rats. Hypertension. 1998; 32: 770–777.
[Abstract/Free Full Text] - Intengan HD, Park J-B, Schiffrin EL. Blood pressure, resistance artery structure and mechanics in DOCA-salt-treated vasopressin-deficient Brattleboro rats: role of endothelin. Hypertension. 1999; 34: 907–913.
[Abstract/Free Full Text] - Hatakeyama H, Miyamori I, Fujita T, Takeda Y, Takeda R, Yamamoto H. Vascular aldosterone: biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells. J Biol Chem. 1994; 289: 24316–24320.
- Lombes M, Oblin ME, Gasc JM, Baulieu EE, Farman N, Bonvalet JP. Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor. Circ Res. 1992; 71: 503–510.
[Abstract/Free Full Text] - Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res. 2000; 87: 840–844.
[Abstract/Free Full Text] - Yura T, Fukunaga M, Khan R, Nassar GN, Badr KF, Montero A. Free radical-generated F2-isoprostane stimulates cell proliferation and endothelin-1 expression on endothelial cells. Kidney Int. 1999; 56: 471–478.[CrossRef][Medline] [Order article via Infotrieve]
- Haas JA, Kreiger JD, Bolterman R, Juncos LA, Romero JC. Low-dose angiotensin II increases free isoprostane levels in plasma. Hypertension. 1999; 34: 983–986.
[Abstract/Free Full Text] - Schnackenberg CG, Welch WJ, Wilcox CS. Normalization of blood pressure and renal vascular resistance in SHR with a membrane-permeable superoxide dismutase mimetic: role of nitric oxide. Hypertension. 1998; 32: 59–64.
[Abstract/Free Full Text] - Münzel T, Kurz S, Rajagopalan S, Thoenes M, Berrington WR, Thompson JA, Freeman BA, Harrison DG. Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase: a new action for an old drug. J Clin Invest. 1996; 15: 98: 1465–1470.[Medline] [Order article via Infotrieve]
- Beswick RA, Dorrance AM, Leite R, Webb RC. NADH/NADPH oxidase and enhanced superoxide production in the mineralocorticoid hypertensive rat. Hypertension. 2001; 38: 1107–1111.
[Abstract/Free Full Text] - Raij L. Hypertension and cardiovascular risk factors: role of the angiotensin II-nitric oxide interaction. Hypertension. 2001; 37: 767–773.
[Abstract/Free Full Text] - Rizzoni D, Porteri E, Castellano M, Bettoni G, Muiesan ML, Muiesan P, Giulini SM, Agabiti-Rosei E. Vascular hypertrophy and remodeling in secondary hypertension. Hypertension. 1996; 28: 785–790.
[Abstract/Free Full Text] - Chatziantoniou C, Boffa JJ, Ardaillou R, Dussaule JC. Nitric oxide inhibition induces early activation of type I collagen gene in renal resistance vessels and glomeruli in transgenic mice: role of endothelin. J Clin Invest. 1998; 101: 2780–2789.[Medline] [Order article via Infotrieve]
- Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res. 2001; 89: 763–771.
[Abstract/Free Full Text] - Barnes PJ, Karin M. Nuclear factor-kappa B: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997; 336: 1066–1071.
[Free Full Text] - Alexander RW. Theodore Cooper Memorial Lecture. Hypertension and the pathogenesis of atherosclerosis. Oxidative stress and the mediation of arterial inflammatory response: a new perspective. Hypertension. 1995; 25: 155–161.
[Abstract/Free Full Text] - Li JS, Schiffrin EL. Effect of chronic treatment of adult spontaneously hypertensive rats with an endothelin receptor antagonist. Hypertension. 1995; 25: 495–500.
[Abstract/Free Full Text] - Li JS, Knafo L, Turgeon A, Garcia R, Schiffrin EL. Effect of endothelin antagonism on blood pressure and vascular structure in renovascular hypertensive rats. Am J Physiol. 1996; 271: H88–H93.[Medline] [Order article via Infotrieve]
- Rossi GP, Cavallin M, Belloni AS, Mazzocchi G, Nussdorfer GG, Pessina AC, Sartore S. Aortic smooth muscle cell phenotypic modulation and fibrillar collagen deposition in angiotensin II–dependent hypertension. Cardiovasc Res. 2002; 55: 178–189.
[Abstract/Free Full Text] - Rossi GP, Sacchetto A, Rizzoni D, Bova S, Porteri E, Mazzocchi G, Belloni AS, Bahcelioglu M, Nussdorfer GG, Pessina AC. Blockade of angiotensin II type 1 receptor and not of endothelin receptor prevents hypertension and cardiovascular disease in transgenic (mREN2)27 rats via adrenocortical steroid-independent mechanisms. Arterioscler Thromb Vasc Biol. 2000; 20: 949–956.
[Abstract/Free Full Text] - Seccia TM, Belloni AS, Kreutz R, Paul M, Nussdorfer GG, Pessina AC, Rossi GP. Cardiac fibrosis occurs early and involves endothelin and AT-1 receptors in hypertension due to endogenous angiotensin II. J Am Coll Cardiol. 2003; 41: 666–673.
[Abstract/Free Full Text]
This article has been cited by other articles:
 |
|
 |
|
  E. L. Schiffrin The Flame That Lights the Fire: Oxidative Stress, Inflammation, and Renal Damage in Angiotensin II-Induced Hypertension Hypertension, August 1, 2008; 52(2): 205 - 206. [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]
|
|
|
|
 |
|
 M. Caprio, B. G. Newfell, A. la Sala, W. Baur, A. Fabbri, G. Rosano, M. E. Mendelsohn, and I. Z. Jaffe Functional Mineralocorticoid Receptors in Human Vascular Endothelial Cells Regulate Intercellular Adhesion Molecule-1 Expression and Promote Leukocyte Adhesion Circ. Res., June 6, 2008; 102(11): 1359 - 1367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Savoia, R. M. Touyz, F. Amiri, and E. L. Schiffrin Selective Mineralocorticoid Receptor Blocker Eplerenone Reduces Resistance Artery Stiffness in Hypertensive Patients Hypertension, February 1, 2008; 51(2): 432 - 439. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Alsafwah, S. P. LaGuardia, M. Arroyo, B. K. Dockery, S. K. Bhattacharya, R. A. Ahokas, and K. P. Newman Congestive Heart Failure is a Systemic Illness: A Role for Minerals and Micronutrients Clin. Med. Res., December 1, 2007; 5(4): 238 - 243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Cooper, A. Whaley-Connell, J. Habibi, Y. Wei, G. Lastra, C. Manrique, S. Stas, and J. R. Sowers Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2009 - H2023. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Grossmann, A. W. Krug, R. Freudinger, S. Mildenberger, K. Voelker, and M. Gekle Aldosterone-induced EGFR expression: interaction between the human mineralocorticoid receptor and the human EGFR promoter Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1790 - E1800. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Wong, F. E. Brennan, M. J. Young, P. J. Fuller, and T. J. Cole A Direct Effect of Aldosterone on Endothelin-1 Gene Expression in Vivo Endocrinology, April 1, 2007; 148(4): 1511 - 1517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. P. Rossi, G. Bernini, G. Desideri, B. Fabris, C. Ferri, G. Giacchetti, C. Letizia, M. Maccario, M. Mannelli, M.-J. Matterello, et al. Renal Damage in Primary Aldosteronism: Results of the PAPY Study Hypertension, August 1, 2006; 48(2): 232 - 238. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Sun, R. A. Ahokas, S. K. Bhattacharya, I. C. Gerling, L. D. Carbone, and K. T. Weber Oxidative stress in aldosteronism Cardiovasc Res, July 15, 2006; 71(2): 300 - 309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Rizzoni, S. Paiardi, L. Rodella, E. Porteri, C. De Ciuceis, R. Rezzani, G. E. M. Boari, F. Zani, M. Miclini, G. A. M. Tiberio, et al. Changes in Extracellular Matrix in Subcutaneous Small Resistance Arteries of Patients with Primary Aldosteronism J. Clin. Endocrinol. Metab., July 1, 2006; 91(7): 2638 - 2642. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Johar, A. C. Cave, A. Narayanapanicker, D. J. Grieve, and A. M. Shah Aldosterone mediates angiotensin II-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase FASEB J, July 1, 2006; 20(9): 1546 - 1548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Masuzawa, S. Jesmin, S. Maeda, S. Zaedi, N. Shimojo, T. Miyauchi, and K. Goto Effect of endothelin dual receptor antagonist on VEGF levels in streptozotocin-induced diabetic rat retina. Experimental Biology and Medicine, June 1, 2006; 231(6): 1090 - 1094. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Schiffrin Effects of Aldosterone on the Vasculature Hypertension, March 1, 2006; 47(3): 312 - 318. [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Yang, L. D. Asico, P. Yu, Z. Wang, J. E. Jones, C. S. Escano, X. Wang, M. T. Quinn, D. R. Sibley, G. G. Romero, et al. D5 dopamine receptor regulation of reactive oxygen species production, NADPH oxidase, and blood pressure Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R96 - R104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|