(Hypertension. 2001;37:801.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Aldosterone Receptor Antagonism Normalizes Vascular Function in Liquorice-Induced Hypertension
From the Institute of Physiology (T.Q.), Cardiovascular Research, University of Zürich, Zürich; the Cardiovascular Center (F.R., T.F.L.), Cardiology, University Hospital Zürich, Zürich; and the Department of Clinical Research (S.S.), Inselspital, University of Bern, Bern, Switzerland.
Correspondence to Thomas F. Lüscher, MD, FRCP, FACC, Professor and Head of Cardiology, University Hospital, CH-8091 Zürich, Switzerland. E-mail cardiotfl{at}GMX.CH
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
The enzyme 11ß-hydroxysteroid dehydrogenase (11ß-HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolizing glucocorticoids to their receptor-inactive 11-dehydro derivatives. The present study investigated the effects of the aldosterone receptor antagonists spironolactone and eplerenone on endothelial function in liquorice-induced hypertension. Glycyrrhizic acid (GA), a recognized inhibitor of 11ß-HSD2, was supplemented to the drinking water (3 g/L) of Wistar-Kyoto rats over a period of 21 days. From days 8 to 21, spironolactone (5.8±0.6 mg · kg-1 · d-1), eplerenone (182±13 mg · kg-1 · d-1), or placebo was added to the chow (n=7 animals per group). Endothelium-dependent or -independent vascular function was assessed as the relaxation of preconstricted aortic rings to acetylcholine or sodium nitroprusside, respectively. In addition, aortic endothelial nitric oxide synthase (eNOS) protein content, nitrate tissue levels, and endothelin-1 (ET-1) protein levels were determined. GA increased systolic blood pressure from 142±8 to 185±9 mm Hg (P<0.01). In the GA group, endothelium-dependent relaxation was impaired compared with that in controls (73±6% versus 99±5%), whereas endothelium-independent relaxation remained unchanged. In the aortas of 11ß-HSD2–deficient rats, eNOS protein content and nitrate tissue levels decreased (1114±128 versus 518±77 µg/g protein, P<0.05). In contrast, aortic ET-1 protein levels were enhanced by GA (308±38 versus 497±47 pg/mg tissue, P<0.05). Both spironolactone and eplerenone normalized blood pressure in animals on GA (142±9 and 143±9 mm Hg, respectively, versus 189±8 mm Hg in the placebo group; P<0.01), restored endothelium-dependent relaxation (96±3% and 97±3%, respectively, P<0.01 versus placebo), blunted the decrease in vascular eNOS protein content and nitrate tissue levels, and normalized vascular ET-1 levels. This is the first study to demonstrate that aldosterone receptor antagonism normalizes blood pressure, prevents upregulation of vascular ET-1, restores NO-mediated endothelial dysfunction, and thus, may advance as a novel and specific therapeutic approach in 11ß-HSD2–deficient hypertension.
Key Words: 11ß-hydroxysteroid dehydrogenase • endothelin-1, endothelium • glycyrrhizic acid • nitric oxide
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The enzyme 11ß-hydroxysteroid dehydrogenase (11ß-HSD) confers mineralocorticoid receptor specificity by metabolizing glucocorticoids to their receptor-inactive 11-dehydro derivatives.1 2 Impaired conversion of cortisol to cortisone results in sodium retention and severe hypertension1 3 and leads to a complex disease named congenital syndrome of apparent mineralocorticoid excess. Because liquorice-derived glycyrrhizic acid (GA) is a well-known inhibitor of 11ß-HSD2, ingestion of GA would result in 11ß-HSD2–deficient hypertension. In addition to its role in the kidney, 11ß-HSD is present in cardiac fibroblasts, coronary vascular smooth muscle, and endothelial cells,4 5 where it is thought to act in a paracrine fashion by modulating local glucocorticoid and mineralocorticoid activity, vascular tone, and endothelial function. Interestingly, reduced urinary excretion of steroid metabolites, suggesting decreased activity of 11ß-HSD, occurs in liquorice-induced as well as in untreated essential hypertension.6
In patients with hypertension, endothelial dysfunction precedes the rise in blood pressure and predisposes them to structural vascular changes.7 8 The endothelium releases vasoactive mediators such as nitric oxide (NO) and endothelin-1 (ET-1), both of which regulate vascular tone9 and structure.10 The aldosterone receptor antagonist spironolactone increases NO bioavailability and vascular relaxation in patients with heart failure.11 This may contribute to its regulatory effects in the treatment of hypertension, for which aldosterone receptor antagonism is a well-established treatment option.12 13 Because spironolactone is beneficial in heart failure,14 15 16 17 a renaissance for aldosterone receptor antagonism treatment has begun,18 including the development of new compounds such as eplerenone19 (Figure 1). Furthermore, there is a good body of evidence for a link between aldosterone and ET, as ET-1 regulates aldosterone secretion from adrenal cells in both healthy individuals20 21 and patients with congestive heart failure.22 Because alterations in GA-induced hypertension are mineralocorticoid receptor mediated, aldosterone receptor antagonism represents a logical therapeutic approach. Hence, the aim of the present study was to elucidate the impact of the established aldosterone receptor antagonist spironolactone in comparison with the recently developed compound eplerenone on endothelial function in GA-induced hypertension.
|
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animals
Male Wistar-Kyoto rats (mean weight 250 g, 13 weeks old) were obtained from RCC, Fuelinsdorf, Switzerland. GA or vehicle was supplemented to the drinking water (3 g/L) over a period of 21 days. From days 8 to 21, the rats were randomly assigned to treatment with either the orally available traditional aldosterone receptor antagonist spironolactone (5.8±0.6 mg · kg-1 · d-1), the novel aldosterone receptor antagonist eplerenone (182±13 mg · kg-1 · d-1), or placebo administered with their chow (n=7 animals per group). Systolic arterial blood pressure and heart rate were measured by the tail-cuff method with a pulse transducer (model LE 5000, Letica).23 The study design and the experimental protocols were approved by the institutional animal care committee (Kommission für Tierversuche des Kantons Zürich, Switzerland) and are in accordance with the American Heart Association guidelines for research animal use.
Tissue Harvesting
Animals were anesthetized with pentobarbital
(50 mg/kg IP) after 3 weeks of treatment, and blood samples were
collected through puncture of the right ventricle. The thoracic aorta
was removed and placed immediately into cold (4°C) modified
Krebs-Ringer bicarbonate solution (in mmol/L: NaCl 118.6, KCl 4.7,
CaCl2 2.5, MgSO4 1.2,
KH2PO4 1.2,
NaHCO3 25.1, EDTA 0.026, and glucose 10.1).
Under a microscope (Leica Wild M3C), vessels were cleaned of adherent
tissue and cut into rings 4 mm long. Some aortic rings were either
placed directly in guanidinium buffer and frozen for later
determination of preproRNA for ET-1, ETA
and ETB receptors by quantitative polymerase
chain reaction or snap-frozen in LN2 for
assessment of tissue ET-1 and nitrate levels.
Organ Chamber Experiments
Vessel rings were suspended from fine tungsten
stirrups (diameter 50 µm), placed in an organ bath filled with 25 mL
of Krebs’ solution, and connected to force transducers (UTC 2, Gould
Statham) for isometric tension recording as described
before.24 After an
equilibration period of 60 minutes, the rings were progressively
stretched to their optimal passive tension (3.0±0.2 g) as assessed by
their response to 100 mmol/L KCl in modified Krebs’
solution.10 Rings were
preconstricted with norepinephrine (NE, 
70% of a
100 mmol/L KCl solution), and relaxations to acetylcholine (ACh,
10-10 to 10-5
mol/L) or sodium nitroprusside (SNP, 10-11
to 10-5 mol/L) were obtained. In
additional experiments, cumulative concentration–response curves to NE
(10-10 to
10-4 mol/L), ET-1
(10-10 to 10-7
mol/L), and bigET-1 (10-9 to
10-7 mol/L) were obtained in quiescent
preparations. All drugs used in the organ bath were obtained from Sigma
Chemical Co except for ET-1 and bigET-1, which were purchased from
Novabiochem/Calbiochem AG. After the experiments, vessel rings were
blotted dry and weighed.
Tissue ET-1 Levels
Aortic tissue and samples of renal medulla and cortex
were snap-frozen in LN2 and kept at -80°C
until assayed. ET-1 was extracted as previously
described.25 26
Nitrite and Nitrate Tissue Levels
Homogenized aortic tissue was
diluted 1:4 in sterile, distilled water and deproteinized (Millipore 10
ultrafiltration membranes). Nitrites and nitrates, the stable end
products of NO
oxidation,27 were quantified
by reverse-phase high-performance liquid
chromatography on an ECE250/4.5 Supersil 100 RP column
(Machery & Nagel) by using ion-pairing chromatography
with photodiode-array detection at 210, 215, and 220 nm as described
before.28
Aortic Endothelial NO Synthase
Protein Content
After incubation with collagenase for 15
minutes at 37°C, the aortic endothelium was scraped
off with a surgical blade. Cells were suspended in Krebs-Ringer
bicarbonate solution and centrifuged at 5000 rpm at 4°C. The
pellet was resuspended in Tris-SDS buffer (Tris-HCl 0.0635 mol/L, pH
6.8, 2% SDS), boiled for 1 minute, and then subjected to 8%
SDS–polyacrylamide gel electrophoresis. Equal amounts of
protein were used for electrophoresis, and comparable loading was
confirmed by silver staining. The protein was then transferred onto
ImmobilonTM-P filter papers (Millipore AG) with use of a semidry
transfer unit. The membranes were subsequently blocked by using 2%
skim milk in phosphate-buffered saline–Tween buffer (0.1% Tween 20,
pH 7.5) for 1 hour and incubated with a 1:1000 dilution of rabbit
anti–endothelial NO synthase (eNOS) 3 IgG antibody
(Santa Cruz Biotechnology Inc). Immunoreactive bands were detected by
an enhanced chemiluminescence system (Amersham). Optical density of
eNOS protein bands was detected by NIH imaging software, and optical
density in control rats was regarded as 100%.
Calculations and Statistical
Analysis
Relaxations to agonists in isolated arteries are
given as percent precontraction in rings that were precontracted with
NE to 70% of the contraction induced by KCl (100 mmol/L).
Contractions are expressed as percentages of 100 mmol/L
KCl–induced contractions, which were obtained at the beginning of each
experiment. Results are presented as mean±SEM. In all
experiments, n equals the number of rats per experiment. For
statistical analysis, the sensitivity of the vessels to the
drugs was expressed as the negative logarithm of the concentration that
caused half-maximal relaxation or contraction
(pD2). Maximal relaxation (expressed as a
percentage of precontraction) or contraction was determined for each
concentration-response curve by nonlinear regression analysis
with the use of MatLab software. For comparison between 2 values, the
unpaired Student’s t test or
the nonparametric Mann-Whitney test was used when
appropriate. For multiple comparisons, results were analyzed by
ANOVA followed by Bonferroni’s
correction.29 Pearson’s
correlation coefficients were calculated by linear regression. A value
of P<0.05 was considered
significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Body Weight, Systolic Blood Pressure, and Heart Rate
Body, kidney, liver, and heart weights did not differ between groups either before or after GA treatment nor during treatment with the aldosterone receptor antagonists. Systolic blood pressure was increased after GA treatment and returned to baseline on administration of either aldosterone receptor antagonist, whereas heart rate was unaltered (Figure 2).
|
Alterations in the ET System
ET-1 Tissue Concentrations
Aortic tissue levels of ET-1 were elevated
(Figure 3; P<0.05 vs
controls) and were normalized by either aldosterone
receptor antagonist
(Figure 3; P<0.05
versus GA).
|
Vascular Reactivity to ET-1
ET-1–induced concentration-dependent contractions were
enhanced after chronic GA feeding and were ameliorated by both
aldosterone receptor antagonists
(Figure 4; P<0.05
versus GA-fed rats).
|
Contractions to NE and KCl
Concentration-dependent contractions to NE were
unaffected by feeding with GA and by treatment with
aldosterone receptor antagonists
(the
Table). Contractile responses to 100 mmol/L KCl
did not differ between the groups (data not
shown).
|
Alterations of the NO System
eNOS Protein Levels
Western blot analysis revealed a decrease in
aortic eNOS protein levels in 11ß-HSD–deficient rats. Aortic eNOS
protein levels were normalized in a similar fashion by both
aldosterone receptor antagonists
(Figure 5).
|
Nitrate Tissue Concentrations
Aortic tissue nitrate concentrations, the stable end
product of NO metabolism, were reduced by 50% by GA
feeding and were normalized by both aldosterone receptor
antagonists
(Figure 6;
P<0.05).
|
P<0.05 vs GA feeding. Results are given as mean±SEM (n=6 animals per group). Spiro indicates spironolactone; EP, eplerenone.
NO-Mediated Endothelial
Function
Endothelium-dependent relaxations of
aortic rings to ACh were blunted after GA treatment and were normalized
by both aldosterone receptor antagonists
(Figure 7). Relaxations to ACh were blocked by
NG-nitro-L-arginine
methyl ester and unaffected by superoxide dismutase or
indomethacin (data not shown).
Endothelium-independent relaxations to SNP were
comparable in all groups
(the
Table).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
These data demonstrate for the first time that in 11ß-HSD hypertension, chronic aldosterone receptor blockade by either spironolactone or the novel compound eplerenone not only normalizes blood pressure but also prevents upregulation of vascular ET-1 and endothelial dysfunction, as reflected by reduced eNOS expression, reduced NO production, and impaired endothelium-dependent relaxations. The activity of 11ß-HSD, which regulates corticosterone (cortisol in humans) access to its receptors and prevents inappropriate occupancy of type 1 mineralocorticoid receptors by glucocorticoids, is decreased in patients with liquorice-induced as well as salt-sensitive hypertension.6 30 In dexamethasone hypertension, the glucocorticoid-induced increase in vascular reactivity precedes the rise in blood pressure, independent of renal mineralocorticoid receptor activation,4 suggesting that 11ß-HSD, which is expressed in vascular smooth muscle4 and endothelial cells,5 may play a role in mediating changes in vascular function. Indeed, we provide here the first evidence that impaired NO formation as well as activation of the vascular ET-1 system contributes to the development of hypertension induced by administration of the 11ß-HSD inhibitor GA.
Activation of the ET system has previously been shown in human hypertension,32 and indirect evidence suggests that increased vascular ET-1 content may be related to hypertensive end-organ damage and remodeling.33 In the present study, aortic protein levels of mature ET-1 were enhanced after GA treatment. Although we previously showed simultaneous activation of the vascular ET system in the aorta and mesenteric resistance arteries in another model of hypertension,10 34 a distinct heterogeneity of ET throughout the vascular bed cannot be excluded in this study. Vascular eNOS protein as well as tissue levels of nitrate/nitrite, the breakdown products of NO, and endothelium-dependent relaxation to ACh were markedly reduced. In contrast to a general reduction in NO bioavailability, nitrate levels in the renal medulla remained stable, which may be ascribed to local regulatory processes.
Because relaxations to ACh were completely blocked by NG-nitro-L-arginine methyl ester and unaffected by superoxide dismutase, these data are compatible with impairment of the endothelial L-arginine/NO pathway in GA-induced hypertension. Therefore, hypertension induced by 11ß-HSD inhibition may involve not only glucocorticoid and mineralocorticoid receptor-mediated modulation of renal function but also marked alterations of the cardiovascular ET-1 and NO systems.
To further elucidate the impact of aldosterone receptor antagonism on GA-induced alterations, the animals were treated with either the established aldosterone receptor antagonist spironolactone or the recently developed aldosterone receptor antagonist eplerenone.35 Both compounds were equally effective in the treatment of 11ß-HSD–deficient hypertension: they normalized blood pressure and reversed activation of the vascular ET-1 system as well as NO bioavailability. The impact of aldosterone receptor antagonism in the treatment of heart failure and hypertension, in particular in states of sodium retention, has been described.36 In this study, we provide the first evidence of full reversibility of the vascular changes that are induced by the 11ß-HSD inhibitor GA by chronic treatment with either spironolactone or eplerenone.
Recent evidence indicates that elevated aldosterone levels play an important role in the development and progression of myocardial fibrosis and hypertrophy in congestive heart failure17 37 38 and that sodium retention is not the primary mechanism of cortisol-induced hypertension.39 These findings may be particularly relevant to the present study, because the current data suggest that reduced activity of 11ß-HSD, due to the generation of endogenous inhibitors or gene defects, could represent an important additional aldosterone-independent mechanism through which inappropriate access of glucocorticoids to vascular receptors may influence vascular tone. The fact that aldosterone receptor antagonism has recently been proved to decrease mortality in severe heart failure17 emphasizes the importance of this therapeutic principle and may further contribute to attempts in evaluation of its underlying mechanisms.
In conclusion, this study demonstrates that the 11ß-HSD inhibitor GA mediates the development of hypertension via decreased bioavailability of NO and activation of the vascular ET-1 system. Because both aldosterone receptor antagonists, spironolactone and eplerenone, normalize blood pressure, prevent upregulation of vascular ET-1, and restore NO-mediated endothelial dysfunction, aldosterone receptor antagonism may provide a novel approach in the treatment of cardiovascular disease associated with reduced activity of 11ß-HSD.
|
Acknowledgments |
|---|
The study was supported by Swiss National Science Foundation grants 32-49648.96 (to S.S.), 32-57225.99 (to F.R.), and 32-51069.97 (to T.F.L.); the Swiss Heart Foundation (to S.S. and F.R.); and Deutscher Akademischer Austauschdienst (to T.Q.).
|
Footnotes |
|---|
1 Both Drs Quaschning and Ruschitzka contributed equally to this work.
Received October 27, 2000; first decision December 11, 2000; accepted December 19, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, Lalouel JM. A chimaeric 11ß-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 1992;355:262–265.[Medline] [Order article via Infotrieve]
2. Stewart PM, Corrie JE, Shackleton CH, Edwards CR. Syndrome of apparent mineralocorticoid excess: a defect in the cortisol-cortisone shuttle. J Clin Invest. 1988;82:340–349.
3. Mune T, Rogerson FM, Nikkila H, Agarwal AK, White PC. Human hypertension caused by mutations in the kidney isozyme of 11ß-hydroxysteroid dehydrogenase. Nat Genet. 1995;10:394–399.[Medline] [Order article via Infotrieve]
4.
Hatakeyama H, Inaba
S, Miyamori I. 11ß-Hydroxysteroid dehydrogenase in cultured human
vascular cells: possible role in the development of hypertension.
Hypertension. 1999;33:1179–1184.
5. Brem AS, Bina RB, King TC, Morris DJ. Localization of 2 11ß-OH steroid dehydrogenase isoforms in aortic endothelial cells. Hypertension. 1998;31(pt 2):459–462.
6.
Soro A, Ingram MC,
Tonolo G, Glorioso N, Fraser R. Evidence of coexisting changes in
11ß-hydroxysteroid dehydrogenase and 5ß-reductase activity in
subjects with untreated essential hypertension.
Hypertension. 1995;25:67–70.
7.
Noll G, Wenzel RR,
Schneider M, Oesch V, Binggeli C, Shaw S, Weidmann P, Lüscher TF.
Increased activation of sympathetic nervous system and endothelin by
mental stress in normotensive offspring of hypertensive parents.
Circulation. 1996;93:866–869.
8.
Taddei S, Virdis A,
Mattei P, Salvetti A. Vasodilatation to acetylcholine in primary and
secondary forms of human hypertension.
Hypertension. 1993;21:929–933.
9. Yanagisawa M, Kurihara H, Kimura S, Goto K, Masaki T. A novel peptide vasoconstrictor, endothelin, is produced by vascular endothelium and modulates smooth muscle Ca2+ channels. J Hypertens Suppl. 1988;6:S188–S191.[Medline] [Order article via Infotrieve]
10. Barton M, d’Uscio LV, Shaw S, Meyer P, Moreau P, Lüscher TF. ET(A) receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy, and endothelial dysfunction in salt-sensitive hypertension. Hypertension. 1998;31(pt 2):499–504.
11.
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.
12. Jeunemaitre X, Chatellier G, Kreft-Jais C, Charru A, DeVries C, Plouin PF, Corvol P, Menard J. Efficacy and tolerance of spironolactone in essential hypertension. Am J Cardiol. 1987;60:820–825.[Medline] [Order article via Infotrieve]
13. Henry M, Wehrlen M, Pelletier B, Capron MH. Spironolactone versus nifedipine in essential hypertension. Am J Cardiol. 1990;65:36K–38K.[Medline] [Order article via Infotrieve]
14. Barr CS, Lang CC, Hanson J, Arnott M, Kennedy N, Struthers AD. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol. 1995;76:1259–1265.[Medline] [Order article via Infotrieve]
15. Struthers AD. Mineralocorticoid receptor blockade in chronic heart failure. J Hum Hypertens. 1995;9:443–446.[Medline] [Order article via Infotrieve]
16. Zannad F. Aldosterone and heart failure. Eur Heart J. 1995;16:98–102.
17.
Pitt B, Zannad F,
Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The
effect of spironolactone on morbidity and mortality in patients with
severe heart failure: Randomized Aldactone Evaluation Study
Investigators. N Engl J
Med. 1999;341:709–717.
18. Brilla CG, Schencking M, Scheer C, Rupp H. Spironolactone: renaissance of anti-aldosterone therapy in heart failure? Schweiz Rundsch Med Prax. 1997;86:566–574.[Medline] [Order article via Infotrieve]
19. Delyani JA. Mineralocorticoid receptor antagonists: the evolution of utility and pharmacology. Kidney Int. 2000;57:1408–1411.[Medline] [Order article via Infotrieve]
20. Cozza EN, Gomez-Sanchez CE. Mechanisms of ET-1 potentiation of angiotensin II stimulation of aldosterone production. Am J Physiol. 1993;265(pt 1):E179–E183.
21. Cavero PG, Miller WL, Heublein DM, Margulies KB, Burnett JC Jr. Endothelin in experimental congestive heart failure in the anesthetized dog. Am J Physiol. 1990;259(pt 2):F312–F317.
22. Sutsch G, Bertel O, Rickenbacher P, Clozel M, Yandle TG, Nicholls MG, Kiowski W. Regulation of aldosterone secretion in patients with chronic congestive heart failure by endothelins. Am J Cardiol. 2000;85:973–976.[Medline] [Order article via Infotrieve]
23.
Webb RC, Vander
AJ, Henry JP. Increased vasodilator responses to acetylcholine in
psychosocial hypertensive mice.
Hypertension. 1987;9:268–276.
24. Lüscher TF, Diederich D, Siebenmann R, Lehmann K, Stulz P, von Segesser L, Yang ZH, Turina M, Gradel E, Weber E. Difference between endothelium-dependent relaxation in arterial and in venous coronary bypass grafts. N Engl J Med. 1988;319:462–467.[Abstract]
25. Shaw SG, Schmid M, Casty A. Critical factors in the radioimmunoassay of endothelin-1, endothelin-3, and big endothelin-1 in human plasma. Anal Biochem. 2000;278:143–149.[Medline] [Order article via Infotrieve]
26. Tuma J, Zaruba K, Studer A, Lüscher TF, Siegenthaler W, Vetter H, Vetter W. Regulation of aldosterone secretion in anephric patients. Klin Wochenschr. 1981;59:27–34.[Medline] [Order article via Infotrieve]
27. Forte P, Copland M, Smith LM, Milne E, Sutherland J, Benjamin N. Basal nitric oxide synthesis in essential hypertension. Lancet. 1997;349:837–842.[Medline] [Order article via Infotrieve]
28.
Barton M,
Haudenschild CC, d’Uscio LV, Shaw S, Munter K, Lüscher TF. Endothelin
ETA receptor blockade restores NO-mediated endothelial
function and inhibits atherosclerosis in apolipoprotein
E-deficient mice. Proc Natl Acad Sci
U S A. 1998;95:14367–14372.
29.
Wallenstein S,
Zucker CL, Fleiss JL. Some statistical methods useful in Circ Res.
Circ Res. 1980;47:1–9.
30. Ferrari P, Krozowski Z. Role of the 11ß-hydroxysteroid dehydrogenase type 2 in blood pressure regulation. Kidney Int. 2000;57:1374–1381.[Medline] [Order article via Infotrieve]
32. Schiffrin EL, Deng LY, Sventek P, Day R. Enhanced expression of endothelin-1 gene in resistance arteries in severe human essential hypertension. J Hypertens. 1997;15:57–63.[Medline] [Order article via Infotrieve]
33.
Ergul S, Parish
DC, Puett D, Ergul A. Racial differences in plasma endothelin-1
concentrations in individuals with essential hypertension [published
erratum appears in Hypertension. 1997;29:912]. Hypertension.
1996;28:652–655.
34.
d’Uscio LV,
Barton M, Shaw S, Moreau P, Lüscher TF. Structure and function of
small arteries in salt-induced hypertension: effects of chronic
endothelin-subtype-A-receptor blockade.
Hypertension. 1997;30:905–911.
35. Albertin G, Malendowicz LK, Tortorella C, Mazzocchi G, Nussdorfer GG. Evidence for a paracrine role of adrenomedullin in the physiological resetting of aldosterone secretion by rat adrenal zona glomerulosa. Peptides. 2000;21:413–417.[Medline] [Order article via Infotrieve]
36. Mantero F, Lucarelli G. Aldosterone antagonists in hypertension and heart failure. Ann Endocrinol (Paris). 2000;61:52–60.[Medline] [Order article via Infotrieve]
37. Slight SH, Joseph J, Ganjam VK, Weber KT. Extra-adrenal mineralocorticoids and cardiovascular tissue. J Mol Cell Cardiol. 1999;31:1175–1184.[Medline] [Order article via Infotrieve]
38. Weber KT. Aldosterone and spironolactone in heart failure. N Engl J Med. 1999;341:753–755.
39. Kelly JJ, Mangos G, Williamson PM, Whitworth JA. Cortisol and hypertension. Clin Exp Pharmacol Physiol Suppl. 1998;25:S51–S56.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  Y. Liu, D. Mladinov, J. L. Pietrusz, K. Usa, and M. Liang Glucocorticoid response elements and 11{beta}-hydroxysteroid dehydrogenases in the regulation of endothelial nitric oxide synthase expression Cardiovasc Res, January 1, 2009; 81(1): 140 - 147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Oyamada, M. Sone, K. Miyashita, K. Park, D. Taura, M. Inuzuka, T. Sonoyama, H. Tsujimoto, Y. Fukunaga, N. Tamura, et al. The Role of Mineralocorticoid Receptor Expression in Brain Remodeling after Cerebral Ischemia Endocrinology, August 1, 2008; 149(8): 3764 - 3777. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Ortiz, M. L. Graciano, J. J. Mullins, and K. D. Mitchell Aldosterone receptor antagonism alleviates proteinuria, but not malignant hypertension, in Cyp1a1-Ren2 transgenic rats Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1584 - F1591. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Ortiz, M. L. Graciano, D. Seth, M. S. Awayda, and L. G. Navar Aldosterone receptor antagonism exacerbates intrarenal angiotensin II augmentation in ANG II-dependent hypertension Am J Physiol Renal Physiol, July 1, 2007; 293(1): F139 - F147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Final Report on the Safety Assessment of Glycyrrhetinic Acid, Potassium Glycyrrhetinate, Disodium Succinoyl Glycyrrhetinate, Glyceryl Glycyrrhetinate, Glycyrrhetinyl Stearate, Stearyl Glycyrrhetinate, Glycyrrhizic Acid, Ammonium Glycyrrhizate, Dipotassium Glycyrrhizate, Disodium Glycyrrhizate, Trisodium Glycyrrhizate, Methyl Glycyrrhizate, and Potassium Glycyrrhizinate International Journal of Toxicology, March 1, 2007; 26(2_suppl): 79 - 112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Arias-Loza, K. Hu, A. Schafer, J. Bauersachs, T. Quaschning, J. Galle, V. Jazbutyte, L. Neyses, G. Ertl, K.-H. Fritzemeier, et al. Medroxyprogesterone Acetate But Not Drospirenone Ablates the Protective Function of 17{beta}-Estradiol in Aldosterone Salt-Treated Rats Hypertension, November 1, 2006; 48(5): 994 - 1001. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Buss, J. Backs, M. M. Kreusser, S. E. Hardt, C. Maser-Gluth, H. A. Katus, and M. Haass Spironolactone Preserves Cardiac Norepinephrine Reuptake in Salt-Sensitive Dahl Rats Endocrinology, May 1, 2006; 147(5): 2526 - 2534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D Struthers and T. M MacDonald Review of aldosterone- and angiotensin II-induced target organ damage and prevention Cardiovasc Res, March 1, 2004; 61(4): 663 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Christy, P. W.F. Hadoke, J. M. Paterson, J. J. Mullins, J. R. Seckl, and B. R. Walker 11{beta}-Hydroxysteroid Dehydrogenase Type 2 in Mouse Aorta: Localization and Influence on Response to Glucocorticoids Hypertension, October 1, 2003; 42(4): 580 - 587. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. B. White, D. Duprez, R. St Hillaire, S. Krause, B. Roniker, J. Kuse-Hamilton, and M. A. Weber Effects of the Selective Aldosterone Blocker Eplerenone Versus the Calcium Antagonist Amlodipine in Systolic Hypertension Hypertension, May 1, 2003; 41(5): 1021 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Lacolley, C. Labat, A. Pujol, C. Delcayre, A. Benetos, and M. Safar Increased Carotid Wall Elastic Modulus and Fibronectin in Aldosterone-Salt-Treated Rats: Effects of Eplerenone Circulation, November 26, 2002; 106(22): 2848 - 2853. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Giannattasio, A. Piperno, M. Failla, A. Vergani, and G. Mancia Effects of Hematocrit Changes on Flow-Mediated and Metabolic Vasodilation in Humans Hypertension, July 1, 2002; 40(1): 74 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Quaschning, F. Ruschitzka, B. Niggli, C. M. B. Lunt, S. Shaw, M. Christ, M. Wehling, and T. F. Luscher Influence of aldosterone vs endothelin receptor antagonism on renovascular function in liquorice-induced hypertension Nephrol. Dial. Transplant., November 1, 2001; 16(11): 2146 - 2151. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||