Published online before print September 10, 2007, doi: 10.1161/HYPERTENSIONAHA.107.093450
(Hypertension. 2007;50:919.)
© 2007 American Heart Association, Inc.
Original Articles |
Mineralocorticoid Receptor Blockade Improves Vasomotor Dysfunction and Vascular Oxidative Stress Early After Myocardial Infarction
From the Medizinische Klinik und Poliklinik I (C.L.S., D.F., P.G., M.L., G.E., J.B.), Universitätsklinikum Würzburg, Bayerische Julius-Maximilians-Universität Würzburg, Germany; and the Department of Physiological Sciences (C.L.S., I.S.), Federal University of Espírito Santo, ES, Brazil.
Correspondence to Johann Bauersachs, MD, Medizinische Klinik I, Universitätsklinikum 1, Julius-Maximilians-Universität, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. E-mail bauersachs_j{at}medizin.uni-wuerzburg.de
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Mineralocorticoid receptor blockade improves mortality early after myocardial infarction (MI). This study investigated the vascular effects of mineralocorticoid receptor blockade in the early phase postinfarction in rats. Starting immediately after coronary ligation, male Wistar rats were treated with placebo or eplerenone (100 mg/kg/d). After 7 days, hemodynamic assessment was performed and endothelial function was determined. Maximum acetylcholine-induced relaxation was significantly attenuated in aortic rings from rats with heart failure after MI, and ameliorated by eplerenone treatment. Endothelium-independent relaxation by DEA-NONOate was similar among the groups. Endothelial NO synthase phosphorylation was reduced in the aorta of MI rats and restored by eplerenone therapy. Angiotensin I-induced vasoconstriction as well as angiotensin-converting enzyme protein levels were enhanced in aortas from MI placebo rats, and reduced by mineralocorticoid receptor inhibition. Aortic reactive oxygen species formation as well as the expression of the NAD(P)H oxidase subunit p22phox were increased after MI and normalized in eplerenone treated rats. In conclusion, mineralocorticoid receptor antagonism improved endothelial dysfunction in the early phase post-MI. Underlying mechanisms involve inhibition of vascular angiotensin-converting enzyme upregulation and improvement of endothelial NO synthase-derived NO bioavailability.
Key Words: aldosterone • acute myocardial infarction • endothelial dysfunction • oxidative stress
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Chronic heart failure is accompanied by endothelial dysfunction.1 Increased production of vascular reactive oxygen species, especially superoxide anion (O2–), as well as diminished antioxidant defense in heart failure contribute to a reduced bioavailability of NO.2 The renin angiotensin aldosterone system (RAAS) is markedly activated and displays a central role in heart failure progression.3,4 Aldosterone synthesis and mineralocorticoid receptors (MR) have been described in the vascular wall.5,6 Aldosterone stimulates vascular ACE expression/activity and potentiates angiotensin II effects.7–10 Angiotensin II and aldosterone stimulate vascular O2– production, promoting NO scavenging and reducing its bioavailability.11–13 In healthy subjects, contradictory effects of aldosterone on endothelial function are reported. Farquharson et al14 showed that intravenous infusion of aldosterone reduced the forearm blood flow response to acetylcholine but did not affect sodium nitroprusside-induced vasodilation, thus inducing acute endothelial dysfunction. Others reported that aldosterone increases forearm blood flow and induces vasodilatation by stimulating NO release through rapid nongenomic effects.15 In a recent investigation, short-term and chronic aldosterone excess did not affect forearm blood flow, but enhanced the vasodilator response to exogenous NO and improved endothelium-dependent NO-mediated vasodilation in the forearm vasculature of healthy men.16,17 However, in subjects with damaged vasculature and endothelial dysfunction, aldosterone infusion induced vasoconstriction, and MR blockade improved NO bioavailability.9,16 Also in experimental chronic heart failure, MR antagonism improved endothelial dysfunction.18
MR antagonism reduces morbidity and mortality among patients with myocardial infarction (MI) complicated by ventricular dysfunction.19–21 However, the underlying mechanisms are still under investigation. Immediate MR antagonism with spironolactone for 1 month improved LV dilation and function in patients with first anterior MI.22 Perrier et al23 showed that MR antagonism prevents the electrical remodeling that precedes cellular hypertrophy after MI such as upregulation of myocardial calcium current (ICa), downregulation of transient outward potassium current (Ito), and prolongation of action potential duration. On the other hand, cardiomyocyte-specific MR overexpression leads to ion channel remodeling, resulting in prolonged ventricular repolarization and in severe ventricular arrhythmias.24
However, no information is available on the effects of MR antagonism in the vascular system early post-MI. Therefore, this study was designed to evaluate the effects of eplerenone on the vasomotor function, RAAS activation, and oxidative stress in rats early after MI induced by coronary artery ligation.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
All procedures were approved by the institutional Animal Research Committee.
Myocardial Infarction, Study Protocol, Hemodynamic Measurements
Left coronary artery ligations were performed in adult male Wistar rats (200 to 250g, Harlan-Winkelmann, Borchen, Germany).25 Starting immediately after coronary ligation, surviving rats were randomly selected for eplerenone (100 mg/kg body wt) or placebo treatment (5% arabic gum) administered by gavage for 7 days. Sham-operated animals received placebo treatment. Eplerenone was used at a dose of 100 mg/kg per day, which is the most commonly used dose for this drug in rats with myocardial infarction25,26 and provided marked end-organ protective effects in the heart and kidney of hypertensive rats.27 Eplerenone selectively blocks the mineralocorticoid receptor. In rats, the IC50 of eplerenone for the glucocorticoid, androgen, progesterone, and estrogen receptors were >10000 nmol/L.28,29 Left ventricular systolic (LVSP) and end-diastolic pressures (LVEDP), mean arterial pressure (MAP), and dP/dt were measured 7 days after MI, under light isoflurane anesthesia and spontaneous respiration, using micromanometer (Millar Instruments). Infarct size was determined as previously described.25 Only rats with extensive infarcts (>40%) were included in the study.
Aldosterone Radioimmunoassay
A blood sample was collected from the right carotid artery. Aldosterone levels were measured by radioimmunoassay (Sorin Biomedica).
Vascular Reactivity Studies
The descending thoracic aorta was dissected after removal of the heart and cleaned of connective tissue. The upper section (
8 mm) was immediately frozen in liquid nitrogen for Western blot analysis. The lower section (6 mm) was used for immediate measurement of O2– production. One ring was frozen in Tissue Teck and another one placed in formalin (4%) and then embedded in paraffin. The remainder was cut into 3-mm rings which were mounted in an organ bath for isometric force measurements. These rings were equilibrated for 30 minutes under a resting tension of 2g in oxygenated (95% O2; 5% CO2) Krebs-Henseleit solution (118 mmol/L NaCl, 4.7 mmol/L KCl, 1.2 mmol/L MgSO4, 1.6 mmol/L CaCl2, 1.2 mmol/L K2HPO4, 25 mmol/L NaHCO3, and 12 mmol/L glucose, pH 7.4; 37°C) containing diclofenac (1µmol/L). Repetitive KCl contractions were performed (with a maximum of 100 mmol/L) until reproducible responses were obtained. Thereafter relaxant responses to cumulative concentrations of acetylcholine and to the endothelium-independent vasodilator 2-(N,N-Diethylamino)-diazenolate-2-oxide (DEA-NONOate) were assessed after preconstriction with phenylephrine to comparable levels. In addition, cumulative concentration-response curves to angiotensin I and II were performed. Angiotensin I vasoconstriction curves were assessed in rings not submitted to DEA NONOate, as NO-releasing compounds could interfere with ACE activity.30
Measurement of Vascular Reactive Oxygen Species
Vascular superoxide anion formation was measured using lucigenin-enhanced chemiluminescence.31 The light reaction between superoxide and lucigenin (5µmol/L) was detected in a luminometer (Wallac) during incubation of rings in a HEPES-modified Krebs buffer (pH 7.4). The specific chemiluminescence signal was expressed as counts per minute per milligram dry weight of tissue (cpm/mg). Moreover, whether eplerenone acts as an antioxidant was evaluated using potassium superoxide (3 mmol/L) in the presence of lucigenin (5 µmol/L). Eplerenone (10–4–10–6 mol/L) had no free radical scavenging and antioxidant activities.
The oxidative fluorescent dye hydroethidine was used to evaluate in situ production of reactive oxygen species as described.31 Unfixed frozen ring segments were cut into 5-µm-thick sections and placed on a glass slide. Hydroethidine (2 µmol/L) was topically applied to each tissue section and coverslipped. Slides were incubated in a light-protected humidified chamber at 37°C for 30 minutes. Stained sections were investigated using a Nikon Eclipse E600 microscope equipped with a C1 confocal scanning head and a 20-fold oil immersion objective. Pictures were acquired and prepared for presentation using the EZ-C1 3.00 software from Nikon. Aortic rings from sham, placebo MI, and eplerenone-treated MI rats were processed and imaged in parallel.
Western Blot Analysis
Aortic samples were homogenized in ice-cold RIPA buffer (NaCl 150 mmol/L; Tris-HCl 50 mmol/L; EDTA 5 mmol/L; Nonidet-P 40 1%; deoxycolate 0.5%; NaF 10 mmol/L; sodium pyrophosphate 10 mmol/L; phenylmethylsulfonyl fluoride 100 mmol/L; aprotinin 2 µg/mL; leopeptin 2 µg/mL). Aortic extracts were mixed with sample loading buffer and separated under reducing conditions on 12% SDS-polyacrylamide gel. Proteins were electro-transferred on polyvinylidene fluoride (PVDF) membranes (Immun-Blot 0.2 µm, Bio-Rad). The bands were detected using a chemiluminescence assay (ECL Plus, Amersham). Primary antibodies used recognize: eNOS (1:2500, Transduction Laboratories, 610296), phosphorylated eNOS at Ser1177 (1:2000, Transduction Laboratories, 612392), Akt (1:2000, Cell Signaling Technology 9272), phosphorylated Akt at Ser473 (1:2000, Cell Signaling Technology, 9271), ACE (1:1000, Abcam, ab11734), p22phox (1:1000, Santa Cruz Biotechnology, sc-11712), MnSOD (1:50000, Abcam, ab13533) and GAPDH (1: 50000, Abcam, ab8245).
Immunohistochemical Analysis
Immunohistochemical localization of phosphorylated eNOS and ACE were determined in frozen or paraffin included aortic 5-µm sections, respectively. Immunohistochemical staining was performed using the same antibodies mentioned above. Briefly, deparaffinization and hydration of paraffin sections or fixation of frozen sections in cold acetone for 5 minutes were followed by pretreatment with 0.3% hydrogen peroxide for 20 minutes to inhibit endogenous peroxidase activity. Subsequently, sections were blocked with 2% horse serum for 30 minutes and incubated with the primary antibody for 1 hour at room temperature. After rinsing with PBS, the sections were incubated for 30 minutes with a biotinylated secondary antibody, followed by incubation with avidin-biotinylated horseradish peroxidase complex (Vectastain ABC, Vector). Serial sections treated with nonimmune IgG did not show any staining. Peroxidase activity positive staining was detected using the DAB detection system (Vector). Sections were counterstained with hematoxylin.
Statistics
Values are presented as means±SEM. Relaxant responses were given as percentage relaxation relative to the preconstriction level. Statistical analysis was performed by 1-way analysis of variance (ANOVA) followed by Fisher post hoc test. Statistical significance was assumed at P<0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Global Parameters and Hemodynamics
Infarct size and body weight were comparable among the experimental groups (Table 1). At 7 days, eplerenone therapy versus placebo significantly reduced LVEDP and improved LV function (Table 1). Circulating aldosterone levels were markedly enhanced after MI and further increased by MR inhibition (Table 1).
|
Vascular Reactivity, Western Blot Analysis, and Immunohistochemistry
Acetylcholine-induced endothelium-dependent relaxation of aortic rings preconstricted with phenylephrine was blunted in aortae from MI rats 7 days postinfarction (Figure 1A; Table 2). Eplerenone treatment restored the maximum relaxation (Emax) to acetylcholine. The endothelium-independent vasorelaxation induced by DEA-NONOate was similar among the groups (Figure 1B; Table 2). Vascular eNOS phosphorylation at Ser1177 was decreased in placebo MI rats, and normalized by eplerenone 7 days postinfarction (Figure 2A and 2B). Myocardial infarction as well as MR inhibition did not affect vascular Akt (Sham Pla, 0.346±0.09; MI Pla, 0.322±0.03; MI Eple, 0.331±0.03 ratio Akt/GAPDH, n=9, P=NS), and phosphorylated Akt (Sham Pla, 0.419±0.09; MI Pla, 0.443±0.05; MI Eple, 0.461±0.04 ratio pAkt/GAPDH, n=9, P=NS), protein levels at 7 days.
|
P<0.05 vs MI Pla.
|
|
Angiotensin I-induced vasoconstriction was significantly enhanced after MI, and partly reduced by eplerenone treatment (Figure 3A; Table 2). The concentration-response curves of the vasoconstrictor angiotensin II were similar among the experimental groups (data not shown). ACE protein levels and immunohistochemical staining were significantly enhanced in aortae of MI placebo and reduced with eplerenone therapy (Figure 3B and 3C).
|
Vascular Reactive Oxygen Species
Superoxide anion formation was significantly increased in the aortae from placebo MI rats, and completely normalized by eplerenone treatment 7 days postinfarction (Figure 4A). Consistently, confocal scanning microscopy images, which used hydroethidium to visualize reactive oxygen species formation, demonstrated enhanced signal intensity throughout the vascular wall in aortic rings from placebo MI rats versus sham, and reduced signals in eplerenone-treated MI rats (Figure 4B). Vascular NAD(P)H oxidase subunit p22phox protein levels were elevated in placebo MI compared with sham-operated rats 7 days postinfarction, and normalized by eplerenone (Figure 5A). Moreover, eplerenone therapy significantly increased vascular MnSOD protein levels 7 days postinfarction (Figure 5B).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Our study demonstrates that immediate MR blockade improves early vasomotor dysfunction and oxidative stress in rats with heart failure after MI. Eplerenone normalized endothelium-dependent maximum relaxation, restored eNOS phosphorylation, and diminished reactive oxygen species formation. Furthermore, MR blockade attenuated the increases in ACE vascular expression and in angiotensin I-induced vasoconstriction.
Impaired endothelium-dependent NO-mediated vasorelaxation contributes to elevated vascular resistance in patients with heart failure and is considered an important predictor of subsequent cardiac events.1,32,33 Aldosterone correlates inversely with arterial compliance, which may be partially related to NO.34 The reduction of endothelium-dependent vasodilatation in response to acetylcholine, through aldosterone-mediated attenuation of NO bioavailability, has been proposed as an important mechanism of endothelial dysfunction.18,35 Clinical trials demonstrated improvement of endothelial vasodilator dysfunction and NO bioactivity by MR blockade in patients with chronic heart failure.9,36 In the current study, eplerenone ameliorated the blunted maximum endothelium-dependent vasorelaxation 7 days after MI, thus underscoring the importance of MR activation for the cardiovascular alterations early after MI. MR blockade restored eNOS phosphorylation at Ser1177, a major regulator of NO production37 which may explain, at least in part, the improved endothelial function early after myocardial infarction. Our study thus provides in vivo evidence of the recently reported aldosterone-mediated downregulation of eNOS phosphorylation in cultured endothelial cells.38
NAD(P)H-dependent vascular oxidase in the aortic wall has been identified as a major source of increased vascular reactive oxygen species and impaired endothelial function in chronic heart failure.2,18,39,40 MR antagonism improved impaired endothelial function by decreasing NAD(P)H oxidase subunit p22phox expression, NAD(P)H oxidase activity and superoxide anion generation in chronic heart failure18 and atherosclerosis.41 The present study demonstrated that MR blockade normalized increased reactive oxygen species production and prevented vascular p22phox upregulation early after MI. Although Nagata et al38 reported enhanced generation of reactive oxygen species through activation of NADPH oxidase by aldosterone in cultured human endothelial cells, reactive oxygen species formation appears to be increased throughout the whole vascular wall after MI, suggesting that also smooth muscle cell NADPH oxidase is involved. Together, these findings underline the central role of MR activation in stimulating vascular reactive oxygen species generation early after MI. Downregulation of ACE by eplerenone therapy may reduce local angiotensin II, which is known to upregulate vascular NADPH oxidase activity.39,42 Moreover, angiotensin II induction of oxidative stress in the vasculature is at least partially mediated by aldosterone.43 Thus, MR antagonism could improve endothelial function also by a reduction of angiotensin II-dependent reactive oxygen species generation.
The imbalance between reactive oxygen species production and its scavenging is considered the main feature of vascular oxidative stress. Inadequate antioxidant reserves contribute to endothelial dysfunction in heart failure.44 The key protective role of the diverse superoxide dismutase (SOD) enzymes in vascular oxidative stress has been widely described, as recently reviewed.45 Addition of exogenous SOD improved endothelium-dependent vasorelaxation.2 MnSOD is 1 of 3 SODs found in mammalian cells which catalyze the dismutation of superoxide to hydrogen peroxide, and considered to be essential for mitochondrial function maintenance and mammalian survival.46,47 MnSOD is abundant in endothelial cells relative to other cell types, and may play an important protective role in oxidative stress situations like ischemia and inflammation.48 MR antagonism promoted MnSOD upregulation early after MI. This effect may account for the reduction in p22phox expression, once this subunit can be upregulated in a positive feedback by reactive oxygen species generation.49 The rise of antioxidant protection prevents NO inactivation by O2– and peroxynitrite (ONOO–) formation and also may break another positive feedback in which ONOO– inactivates MnSOD.50 Furthermore, aldosterone has recently been shown to downregulate glucose-6-phosphate dehydrogenase activity, resulting in reduced NO levels, increased reactive oxygen species, and impaired vascular reactivity.51 Coordinated, all these beneficial effects could account for the positive balance between NO and O2– promoted by eplerenone therapy.
Aldosterone stimulates ACE expression and activity in rat neonatal cardiac myocytes, thus increasing the conversion of angiotensin I to angiotensin II.9,52 Furthermore, the induction of ACE by aldosterone was recently described in cultured rat endothelial cells via a MR-dependent pathway.10 This mechanism likely contributes to enhanced vasoconstrictor response to angiotensin I and vascular ACE upregulation, as we observed markedly elevated circulating aldosterone levels after MI, and MR inhibition prevented ACE upregulation and partially reduced angiotensin I-induced vasoconstriction. Thus, the positive feedback loop for a local RAAS, namely aldosterone-mediated ACE upregulation, is likely to be involved in the development of endothelial dysfunction and vascular injury induced by aldosterone early after MI. Although there is controversy about the main enzyme responsible for the angiotensin I/angiotensin II conversion, ACE seems to be the main one in rats.53,54
Immediate MR blockade reduced LV filling pressure and ameliorated LV contractile dysfunction 7 days postinfarction. Although the sequence of events cannot easily be elucidated in the animal model, these cardiac effects of MR antagonism are likely to contribute to the beneficial effects on endothelial dysfunction and oxidative stress early postinfarction.
In conclusion, we show for the first time that MR blockade with eplerenone improved endothelial dysfunction in the early phase post-MI. Underlying mechanisms involve inhibition of vascular ACE upregulation and improvement of eNOS-derived NO bioavailability.
Perspectives
In the present study, MR blockade with eplerenone improved endothelial dysfunction, NO bioavailability, and oxidative stress early after experimental MI. In addition to beneficial modulation of electrical remodeling these vascular effects of MR blockade may contribute to the marked reduction of mortality by eplerenone treatment within 30 days in patients with acute MI complicated by heart failure. Impaired endothelial vasodilator function is an independent predictor of clinical deterioration and death in heart failure. In EPHESUS the patients randomized early to treatment derived more benefit than that randomized late, however, even better effects may be achieved by instant eplerenone therapy postinfarction.
|
Acknowledgments |
|---|
Sources of Funding
This work was supported by the Deutsche Forschungsgemeinschaft (SFB355 B10 to J.B.) and by Pfizer (Karlsruhe, Germany). Additional support was provided by a fellowship from the National Council for Scientific and Technological Development (CNPq, Brazil), grant 200291/2004-1 (to C.L.S.).
Disclosures
D.F. and J.B. have a significant research grant from Pfizer related to eplerenone. The remaining authors report no conflicts.
|
Footnotes |
|---|
C.L.S. and D.F. contributed equally to this work.
Received May 8, 2007; first decision June 6, 2007; accepted August 23, 2007.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Kubo SH, Rector TS, Bank AJ, Williams RE, Heifetz SM. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation. 1991; 84: 1589–1596.
2. Bauersachs J, Bouloumie A, Fraccarollo D, Hu K, Busse R, Ertl G. Endothelial dysfunction in chronic myocardial infarction despite increased vascular endothelial nitric oxide synthase and soluble guanylate cyclase expression: role of enhanced vascular superoxide production. Circulation. 1999; 100: 292–298.
3. Wollert KC, Drexler H. The renin-angiotensin system and experimental heart failure. Cardiovasc Res. 1999; 43: 838–849.
4. Dzau VJ, Hirsch AT. Emerging role of the tissue renin-angiotensin systems in congestive heart failure. Eur Heart J. 1990; 11 Suppl B: 65–71.
5. Takeda Y, Miyamori I, Yoneda T, Iki K, Hatakeyama H, Blair IA, Hsieh FY, Takeda R. Production of aldosterone in isolated rat blood vessels. Hypertension. 1995; 25: 170–173.
6. Funder JW, Pearce PT, Smith R, Campbell J. Vascular type I aldosterone binding sites are physiological mineralocorticoid receptors. Endocrinology. 1989; 125: 2224–2226.
7. Xiao F, Puddefoot JR, Vinson GP. Aldosterone mediates angiotensin II-stimulated rat vascular smooth muscle cell proliferation. J Endocrinol. 2000; 165: 533–536.[Abstract]
8. Mazak I, Fiebeler A, Muller DN, Park JK, Shagdarsuren E, Lindschau C, Dechend R, Viedt C, Pilz B, Haller H, Luft FC. Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cells. Circulation. 2004; 109: 2792–2800.
9. 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.
10. Sugiyama T, Yoshimoto T, Tsuchiya K, Gochou N, Hirono Y, Tateno T, Fukai N, Shichiri M, Hirata Y. Aldosterone induces angiotensin converting enzyme gene expression via a JAK2-dependent pathway in rat endothelial cells. Endocrinology. 2005; 146: 3900–3906.
11. Seshiah PN, Weber DS, Rocic P, Valppu L, Taniyama Y, Griendling KK. Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators. Circ Res. 2002; 91: 406–413.
12. Keidar S, Kaplan M, Pavlotzky E, Coleman R, Hayek T, Hamoud S, Aviram M. Aldosterone administration to mice stimulates macrophage NADPH oxidase and increases atherosclerosis development: a possible role for angiotensin-converting enzyme and the receptors for angiotensin II and aldosterone. Circulation. 2004; 109: 2213–2220.
13. Gryglewski RJ, Palmer RM, Moncada S. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature. 1986; 320: 454–456.[CrossRef][Medline] [Order article via Infotrieve]
14. Farquharson CA, Struthers AD. Aldosterone induces acute endothelial dysfunction in vivo in humans: evidence for an aldosterone-induced vasculopathy. Clin Sci (Lond). 2002; 103: 425–431.[Medline] [Order article via Infotrieve]
15. Schmidt BM, Oehmer S, Delles C, Bratke R, Schneider MP, Klingbeil A, Fleischmann EH, Schmieder RE. Rapid nongenomic effects of aldosterone on human forearm vasculature. Hypertension. 2003; 42: 156–160.
16. Adler GK, Williams GH. Aldosterone: villain or protector? Hypertension. 2007; 50: 31–32.
17. Nietlispach F, Julius B, Schindler R, Bernheim A, Binkert C, Kiowski W, Brunner-La Rocca HP. Influence of acute and chronic mineralocorticoid excess on endothelial function in healthy men. Hypertension. 2007; 50: 82–88.
18. Bauersachs J, Heck M, Fraccarollo D, Hildemann SK, Ertl G, Wehling M, Christ M. Addition of spironolactone to angiotensin-converting enzyme inhibition in heart failure improves endothelial vasomotor dysfunction: role of vascular superoxide anion formation and endothelial nitric oxide synthase expression. J Am Coll Cardiol. 2002; 39: 351–358.
19. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309–1321.
20. Pitt B, White H, Nicolau J, Martinez F, Gheorghiade M, Aschermann M, van Veldhuisen DJ, Zannad F, Krum H, Mukherjee R, Vincent J. Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am Coll Cardiol. 2005; 46: 425–431.
21. Pitt B, Pitt GS. Added benefit of mineralocorticoid receptor blockade in the primary prevention of sudden cardiac death. Circulation. 2007; 115: 2976–2982.
22. Hayashi M, Tsutamoto T, Wada A, Tsutsui T, Ishii C, Ohno K, Fujii M, Taniguchi A, Hamatani T, Nozato Y, Kataoka K, Morigami N, Ohnishi M, Kinoshita M, Horie M. Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction. Circulation. 2003; 107: 2559–2565.
23. Perrier E, Kerfant BG, Lalevee N, Bideaux P, Rossier MF, Richard S, Gomez AM, Benitah JP. Mineralocorticoid receptor antagonism prevents the electrical remodeling that precedes cellular hypertrophy after myocardial infarction. Circulation. 2004; 110: 776–783.
24. Ouvrard-Pascaud A, Sainte-Marie Y, Benitah JP, Perrier R, Soukaseum C, Cat AN, Royer A, Le Quang K, Charpentier F, Demolombe S, Mechta-Grigoriou F, Beggah AT, Maison-Blanche P, Oblin ME, Delcayre C, Fishman GI, Farman N, Escoubet B, Jaisser F. Conditional mineralocorticoid receptor expression in the heart leads to life-threatening arrhythmias. Circulation. 2005; 111: 3025–3033.
25. Fraccarollo D, Galuppo P, Hildemann S, Christ M, Ertl G, Bauersachs J. Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction. J Am Coll Cardiol. 2003; 42: 1666–1673.
26. Enomoto S, Yoshiyama M, Omura T, Matsumoto R, Kusuyama T, Kim S, Izumi Y, Akioka K, Iwao H, Takeuchi K, Yoshikawa J. Effects of eplerenone on transcriptional factors and mRNA expression related to cardiac remodelling after myocardial infarction. Heart. 2005; 91: 1595–1600.
27. Rocha R, Rudolph AE, Frierdich GE, Nachowiak DA, Kekec BK, Blomme EA, McMahon EG, Delyani JA. Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol. 2002; 283: H1802–H1810.
28. Brown NJ. Eplerenone: cardiovascular protection. Circulation. 2003; 107: 2512–2518.
29. de Gasparo M, Joss U, Ramjoue HP, Whitebread SE, Haenni H, Schenkel L, Kraehenbuehl C, Biollaz M, Grob J, Schmidlin J, Wieland P, Wehrli HU. Three new epoxy-spirolactone derivatives: characterization in vivo and in vitro. J Pharmacol Exp Ther. 1987; 240: 650–656.
30. Ackermann A, Fernandez-Alfonso MS, Sanchez de Rojas R, Ortega T, Paul M, Gonzalez C. Modulation of angiotensin-converting enzyme by nitric oxide. Br J Pharmacol. 1998; 124: 291–298.[CrossRef][Medline] [Order article via Infotrieve]
31. Bendall JK, Rinze R, Adlam D, Tatham AL, de Bono J, Channon KM. Endothelial Nox2 overexpression potentiates vascular oxidative stress and hemodynamic response to angiotensin II: studies in endothelial-targeted Nox2 transgenic mice. Circ Res. 2007; 100: 1016–1025.
32. Katz SD, Hryniewicz K, Hriljac I, Balidemaj K, Dimayuga C, Hudaihed A, Yasskiy A. Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure. Circulation. 2005; 111: 310–314.
33. Fischer D, Rossa S, Landmesser U, Spiekermann S, Engberding N, Hornig B, Drexler H. Endothelial dysfunction in patients with chronic heart failure is independently associated with increased incidence of hospitalization, cardiac transplantation, or death. Eur Heart J. 2005; 26: 65–69.
34. Duprez DA, De Buyzere ML, Rietzschel ER, Taes Y, Clement DL, Morgan D, Cohn JN. Inverse relationship between aldosterone and large artery compliance in chronically treated heart failure patients. Eur Heart J. 1998; 19: 1371–1376.
35. Duprez D, De Buyzere M, Rietzschel ER, Clement DL. Aldosterone and vascular damage. Curr Hypertens Rep. 2000; 2: 327–334.[Medline] [Order article via Infotrieve]
36. Macdonald JE, Kennedy N, Struthers AD. Effects of spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other prognostic markers in patients with mild heart failure already taking optimal treatment. Heart. 2004; 90: 765–770.
37. Fleming I, Busse R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol. 2003; 284: R1–R12.
38. Nagata D, Takahashi M, Sawai K, Tagami T, Usui T, Shimatsu A, Hirata Y, Naruse M. Molecular mechanism of the inhibitory effect of aldosterone on endothelial NO synthase activity. Hypertension. 2006; 48: 165–171.
39. Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest. 1996; 97: 1916–1923.[Medline] [Order article via Infotrieve]
40. Fukui T, Ishizaka N, Rajagopalan S, Laursen JB, Capers QT, Taylor WR, Harrison DG, de Leon H, Wilcox JN, Griendling KK. p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats. Circ Res. 1997; 80: 45–51.
41. Rajagopalan S, Duquaine D, King S, Pitt B, Patel P. Mineralocorticoid receptor antagonism in experimental atherosclerosis. Circulation. 2002; 105: 2212–2216.
42. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994; 74: 1141–1148.
43. Virdis A, Neves MF, Amiri F, Viel E, Touyz RM, Schiffrin EL. Spironolactone improves angiotensin-induced vascular changes and oxidative stress. Hypertension. 2002; 40: 504–510.
44. Indik JH, Goldman S, Gaballa MA. Oxidative stress contributes to vascular endothelial dysfunction in heart failure. Am J Physiol. 2001; 281: H1767–H1770.
45. Wassmann S, Wassmann K, Nickenig G. Modulation of oxidant and antioxidant enzyme expression and function in vascular cells. Hypertension. 2004; 44: 381–386.
46. Li Y, Huang TT, Carlson EJ, Melov S, Ursell PC, Olson JL, Noble LJ, Yoshimura MP, Berger C, Chan PH, Wallace DC, Epstein CJ. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet. 1995; 11: 376–381.[CrossRef][Medline] [Order article via Infotrieve]
47. Copin JC, Gasche Y, Chan PH. Overexpression of copper/zinc superoxide dismutase does not prevent neonatal lethality in mutant mice that lack manganese superoxide dismutase. Free Radic Biol Med. 2000; 28: 1571–1576.[CrossRef][Medline] [Order article via Infotrieve]
48. Suzuki K, Tatsumi H, Satoh S, Senda T, Nakata T, Fujii J, Taniguchi N. Manganese-superoxide dismutase in endothelial cells: localization and mechanism of induction. Am J Physiol. 1993; 265: H1173–H1178.[Medline] [Order article via Infotrieve]
49. Djordjevic T, Pogrebniak A, BelAiba RS, Bonello S, Wotzlaw C, Acker H, Hess J, Gorlach A. The expression of the NADPH oxidase subunit p22phox is regulated by a redox-sensitive pathway in endothelial cells. Free Radic Biol Med. 2005; 38: 616–630.[CrossRef][Medline] [Order article via Infotrieve]
50. Yamakura F, Taka H, Fujimura T, Murayama K. Inactivation of human manganese-superoxide dismutase by peroxynitrite is caused by exclusive nitration of tyrosine 34 to 3-nitrotyrosine. J Biol Chem. 1998; 273: 14085–14089.
51. Leopold JA, Dam A, Maron BA, Scribner AW, Liao R, Handy DE, Stanton RC, Pitt B, Loscalzo J. Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. Nat Med. 2007; 13: 189–197.[CrossRef][Medline] [Order article via Infotrieve]
52. Wang J, Yu L, Solenberg PJ, Gelbert L, Geringer CD, Steinberg MI. Aldosterone stimulates angiotensin-converting enzyme expression and activity in rat neonatal cardiac myocytes. J Card Fail. 2002; 8: 167–174.[CrossRef][Medline] [Order article via Infotrieve]
53. Okunishi H, Oka Y, Shiota N, Kawamoto T, Song K, Miyazaki M. Marked species-difference in the vascular angiotensin II-forming pathways: humans versus rodents. Jpn J Pharmacol. 1993; 62: 207–210.[Medline] [Order article via Infotrieve]
54. Inoue K, Nishimura H, Kubota J, Kawamura K. Alternative angiotensin II formation in rat arteries occurs only at very high concentrations of angiotensin I. Hypertension. 1999; 34: 525–530.
Related Article:
Hypertension 2007 50: 842-843.
This article has been cited by other articles:
 |
|
 |
|
  F. R. Perez, F. Venegas, M. Gonzalez, S. Andres, C. Vallejos, G. Riquelme, J. Sierralta, and L. Michea Endothelial Epithelial Sodium Channel Inhibition Activates Endothelial Nitric Oxide Synthase via Phosphoinositide 3-Kinase/Akt in Small-Diameter Mesenteric Arteries Hypertension, June 1, 2009; 53(6): 1000 - 1007. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Mulder, V. Mellin, J. Favre, M. Vercauteren, I. Remy-Jouet, C. Monteil, V. Richard, S. Renet, J. P. Henry, A. Y. Jeng, et al. Aldosterone synthase inhibition improves cardiovascular function and structure in rats with heart failure: a comparison with spironolactone Eur. Heart J., September 1, 2008; 29(17): 2171 - 2179. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Fraccarollo, P. Galuppo, S. Schraut, S. Kneitz, N. van Rooijen, G. Ertl, and J. Bauersachs Immediate Mineralocorticoid Receptor Blockade Improves Myocardial Infarct Healing by Modulation of the Inflammatory Response Hypertension, April 1, 2008; 51(4): 905 - 914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yu, S.-G. Wei, Z.-H. Zhang, E. Gomez-Sanchez, R. M. Weiss, and R. B. Felder Does Aldosterone Upregulate the Brain Renin-Angiotensin System in Rats With Heart Failure? Hypertension, March 1, 2008; 51(3): 727 - 733. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Bauersachs and D. Fraccarollo More NO-No More ROS: Combined Selective Mineralocorticoid Receptor Blockade and Angiotensin-Converting Enzyme Inhibition for Vascular Protection Hypertension, March 1, 2008; 51(3): 624 - 625. [Full Text] [PDF]
|
|
|
|
|
|
R. P. Brandes Avoiding Vicious Circles: Mineralocorticoid Receptor Antagonism Prevents Vascular Oxidative Stress Early After Myocardial Infarction Hypertension, November 1, 2007; 50(5): 842 - 843. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||