(Circulation. 2000;101:594.)
© 2000 American Heart Association, Inc.
Brief Rapid Communications |
Spironolactone Increases Nitric Oxide Bioactivity, Improves Endothelial Vasodilator Dysfunction, and Suppresses Vascular Angiotensin I/Angiotensin II Conversion in Patients With Chronic Heart Failure
From the University Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, Dundee, UK.
Correspondence to Dr Colin Farquharson, Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. E-mail c.a.j.farquharson{at}dundee.ac.uk
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Abstract |
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Background—The RALES study showed that spironolactone, added to conventional therapy for chronic heart failure, dramatically reduced mortality. We tested the hypothesis that this benefit was partially due to improvement in endothelial function and/or to amplified suppression of the vascular renin-angiotensin axis.
Methods and Results—We performed a randomized, placebo-controlled, double-blind crossover study on 10 patients with NYHA class II to III chronic heart failure on standard diuretic/ACE inhibitor therapy, comparing 50 mg/d spironolactone (1 month) versus placebo. Forearm vasculature endothelial function was assessed by bilateral forearm venous occlusion plethysmography using acetylcholine and N-monomethyl-L-arginine (L-NMMA), with sodium nitroprusside as a control vasodilator. Also, vascular ACE activity was assessed by use of angiotensin (Ang) I, with Ang II as a control vasoconstrictor. Spironolactone significantly increased the forearm blood flow response to acetylcholine (percentage change in forearm blood flow [mean±SEM], 177±29% versus 95±20%, spironolactone versus placebo; P<0.001), with an associated increase in vasoconstriction due to L-NMMA (-35±6% versus -18±4%; P<0.05). The Ang I response was also significantly reduced with spironolactone (P<0.05), with Ang II responses unaltered.
Conclusions—Spironolactone improves endothelial dysfunction, increases NO bioactivity, and inhibits vascular Ang I/Ang II conversion in patients with heart failure, providing novel mechanisms for its beneficial effect on cardiovascular mortality.
Key Words: spironolactone • endothelium • angiotensin • enzymes • heart failure • nitric oxide
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Introduction |
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Recently, the Randomized ALdactone Evaluation Study (RALES) trial was stopped prematurely because of a significant 30% survival advantage in patients receiving spironolactone in addition to standard therapy for chronic heart failure (CHF), including diuretics and ACE inhibition.1 Mechanisms contributing to this beneficial effect include blocking of the effect of aldosterone on potassium/magnesium loss, autonomic function, and myocardial fibrosis.2 Recent experimental observations suggest a whole new adverse effect of aldosterone, namely on the vasculature. The most intriguing data are in 1 tissue culture study in which aldosterone inhibited NO release.3 Experimental evidence also suggests that aldosterone amplifies tissue ACE and angiotensin (Ang) II responses.4 5 6 We therefore set out to see whether such novel vascular effects could be demonstrated for aldosterone in humans in vivo. We focused on patients with CHF so that our findings were directly relevant to the RALES study.
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Methods |
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Study Experimental Design
Ten male patients with stable mild to moderate CHF secondary to ischemic cardiomyopathy (Table 1
) gave written informed consent
to participate in the study, which had prior approval by the Tayside
Committee on Medical Research Ethics. One month of therapy with
spironolactone 50 mg/d was compared with placebo in a randomized,
placebo-controlled, double-blind, crossover trial with a 2-week washout
period between treatment phases. Other cardiovascular
medication remained constant throughout the duration of the study. Each
subject attended for 2 vascular studies, performed at the end of each
treatment phase, as detailed below.
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Vascular Studies
After an overnight fast, patients attended a
temperature-controlled laboratory (24°C to 26°C) at 8
AM. All cardiovascular medications were
taken immediately before the start of the study visit. After 20 minutes
of supine rest, the nondominant brachial artery was cannulated with a
27-gauge steel needle mounted onto a 16-gauge epidural catheter under
local anesthesia. After 30 minutes of saline
infusion, baseline forearm blood flow (FBF) was measured by
forearm venous-occlusion plethysmography,7 as described
before.8 Drugs were then infused (see below) into the
study arm with a constant-rate infuser. FBFs were measured at each
baseline and during the last 2 minutes of each drug infusion. Blood
pressure was measured in the noninfused (control) arm at regular
intervals throughout the study.
Drug Infusions
First, acetylcholine (Miochol, CIBAVision) was infused at 25,
50, and 100 nmol/min, each for 5 minutes. This was followed by sodium
nitroprusside (David Bull Laboratories) at 4.2, 12.6, and 37.8
nmol/min, each for 5 minutes, and then
NG-monomethyl-L-arginine
(L-NMMA; Clinalfa) at 1, 2, and 4 µmol/min for 5 minutes each.
This was followed by Ang I (Clinalfa) at 64, 256, and 1024 pmol/min for
7 minutes each, and finally, Ang II (Clinalfa) was infused at 16, 64,
and 256 pmol/min for 7 minutes each. Between the different drugs, the
drug infusion set was flushed with saline for 20 to 30 minutes to allow
sufficient time for the FBF to return to baseline values.
Acetylcholine is an endothelium-dependent vasodilator, and sodium nitroprusside is an endothelium-independent vasodilator. L-NMMA is a competitive NO synthase inhibitor. Ang I exerts vasoconstriction in this forearm model only through conversion in the vasculature to Ang II, and therefore any vasoconstriction elicited reflects vascular Ang I/Ang II conversion.8
Statistical Analysis
FBF values (expressed as mL ·
min-1 · 100 mL forearm
volume-1) were converted to the ratio between
the increase in blood flow in the infused arm and the blood flow in the
control arm, expressed as percentage change in FBF from the baseline
immediately preceding each drug administration (mean±SEM).
Clinical characteristics between study visits were compared by Student’s paired t test, and FBF measurements for individual subjects were compared between treatments by 2-way ANOVA with repeated measures with correction for multiple comparisons for within-group effects. A value of P<0.05 was considered significant.
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Results |
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Subject Characteristics
A trend toward increased baseline FBF was observed in the spironolactone-treatment group compared with the placebo group, although this difference was statistically nonsignificant (2.9±0.6 versus 3.8±0.6 mL · min-1 · 100 mL-1, placebo versus spironolactone; P=0.17). Baseline FBF values between the arms preceding each drug infusion were not different, indicative of adequate drug washout between each infusion phase.
There were also no significant changes in blood pressure either between
or during each study day (Table 2). Urea,
creatinine, and plasma potassium assays are also shown in
Table 2. There was no observed subjective or objective change in
NYHA functional class between the 2 treatment periods.
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Forearm Vascular Responses
Spironolactone produced a significant improvement in
acetylcholine-mediated endothelium-dependent
vasodilation (P<0.001 for difference between whole
dose-response curves, Figure 1).
Similarly, the vasoconstrictive response to L-NMMA was
augmented with spironolactone therapy (P<0.05). In
contrast, spironolactone had no effect on sodium nitroprusside
responses (P=0.84).
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) or spironolactone (
)
therapy. Values are mean±SEM. *P<0.05,
**P<0.001 for differences between treatments.
A significant reduction in vasoconstriction was seen between
spironolactone and placebo with regard to Ang I (see Figure 2, P<0.05). However, there
was no significant difference between the treatment groups with regard
to the forearm responses to the control vasoconstrictor Ang II
(P=0.89).
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Discussion |
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Our principal finding is that tonic NO bioactivity was significantly improved by spironolactone in CHF. Also, spironolactone attenuated Ang I– but not Ang II–mediated vasoconstriction, implying that spironolactone causes further inhibition of vascular Ang I/Ang II conversion even in the presence of chronic ACE inhibition. Blood pressure and NYHA functional class were unaffected by spironolactone, which implies that systemic effects per se were not responsible for our findings.
Two pieces of data support the concept that spironolactone improves endothelial function. First, aldosterone reduces NO bioactivity in tissue culture when stimulated by cytokines.3 Second, aldosterone correlates inversely with arterial compliance, which may be related in part to NO.9 Our study also suggests that aldosterone upregulates vascular conversion of Ang I into Ang II in CHF despite ACE inhibition. This is intriguing, implying that feedback amplification occurs in the vascular renin-angiotensin system as opposed to the more usual feedback inhibition. Before our study, experimental evidence supported this mechanism, with the one exception that in tissue culture, aldosterone also amplified the response to Ang II, whereas we did not find this.4 5 6 One might think that the improved NO production would complicate interpretation of our Ang I/Ang II responses, but the fact that Ang II responses were unaltered by spironolactone suggests that a specific effect on vascular Ang I conversion was observed rather than a general effect on vasoconstrictor responses. Furthermore, we have previously shown that NO does not alter vascular Ang I conversion itself in vivo in humans.10
From this study, it is impossible to say whether the spironolactone-induced improvement in NO activity accounts for the whole improvement in endothelial vasodilator dysfunction or whether spironolactone has additional effects on other endothelium-derived vasodilating substances, such as prostacyclin or endothelium-derived hyperpolarizing factor (EDHF). It is unlikely but not impossible that some of the improvement observed in acetylcholine responses was mediated by prostaglandins, because all subjects were taking soluble aspirin chronically (mean treatment duration, 6.5 years) at a dose known to cause vascular cyclooxygenase inhibition in humans.11 EDHF is virtually impossible to study in our forearm model at present for various reasons. It is currently contentious whether this agent is potassium ion,12 free fatty acid/arachidonic acid metabolites, or other putative agents. Barium can block the passage of this potassium-ion/EDHF in some fashion, but barium may not be pharmacologically specific for EDHF alone in our model, and its potential toxicity may limit in vivo arterial investigation. Therefore, we state that endothelial vasodilator dysfunction was improved by spironolactone and that basal NO bioactivity was improved by spironolactone, but we cannot exclude additional effects on prostacyclin or EDHF.
In conclusion, we have shown that spironolactone improves vascular function by novel mechanisms that are likely to contribute importantly to the positive RALES results. Indeed, improving endothelial dysfunction has recently been suggested as a new therapeutic target in CHF.13 Spironolactone appears to be a treatment that not only achieves that target but also reduces total mortality in patients with heart failure.
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Acknowledgments |
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Dr Farquharson was supported by the British Heart Foundation during this study.
Received September 1, 1999; revision received November 23, 1999; accepted December 6, 1999.
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References |
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1. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J, for the Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709–717.
2. Struthers AD. Why does spironolactone improve mortality over and above an ACE-inhibitor in chronic heart failure? Br J Clin Pharmacol. 1999;47:479–482.[Medline] [Order article via Infotrieve]
3. Ikeda U, Kanbe T, Nakayama I, Kawahara Y, Yokoyama M, Shimada K. Aldosterone inhibits nitric oxide synthesis in rat vascular smooth muscle cells induced by interleukin-1ß. Eur J Pharmacol. 1995;290:69–73.[Medline] [Order article via Infotrieve]
4. Sun Y, Ratajska A, Zhou G, Weber KT. Angiotensin converting enzyme and myocardial fibrosis in the rat receiving angiotensin II or aldosterone. J Lab Clin Med. 1993;122:395–403.[Medline] [Order article via Infotrieve]
5. Sun Y, Weber KT. Angiotensin II and aldosterone receptor binding in rat heart and kidney: response to chronic angiotensin II or aldosterone administration. J Lab Clin Med. 1993;122:404–411.[Medline] [Order article via Infotrieve]
6.
Ullian ME, Schelling JR, Linas SL.
Aldosterone enhances angiotensin II receptor
binding and inositol phosphate responses. Hypertension. 1992;20:67–73.
7.
Benjamin N, Calver A, Collier J, Robinson B, Vallance
P, Webb DJ. Measuring forearm blood flow and interpreting the responses
to drugs and mediators. Hypertension. 1995;25:918–923.
8.
Davidson NC, Barr CS, Struthers AD. C-type
natriuretic peptide: an endogenous
inhibitor of vascular angiotensin-converting
enzyme activity. Circulation. 1996;93:1155–1159.
9.
Duprez DA, DeBuyzere 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.
10. Davidson NC, Struthers AD. Nitric oxide regulates renin release during salt depletion but does not alter angiotensin responses in normal humans. J Cardiovasc Pharmacol Ther. 1999;4:9–14.
11.
Kyrle PA, Eichler HG, Jager U, Lechner K. Inhibition of
prostacyclin and thromboxane A2
generation by low-dose aspirin at the site of plug formation in man in
vivo. Circulation. 1987;75:1025–1029.
12. Edwards G, Dora KA, Gardener MJ, Garland CJ, Weston AH. K+ is an endothelium-derived hyperpolarising factor in rat arteries. Nature. 1998;396:269–272.[Medline] [Order article via Infotrieve]
13.
Drexler H. Endothelium as a therapeutic
target in heart failure. Circulation. 1998;98:2652–2655.
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T. Karram, A. Abbasi, S. Keidar, E. Golomb, I. Hochberg, J. Winaver, A. Hoffman, and Z. Abassi Effects of spironolactone and eprosartan on cardiac remodeling and angiotensin-converting enzyme isoforms in rats with experimental heart failure Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1351 - H1358. [Abstract] [Full Text] [PDF]
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J. W. Funder Relative Aldosterone Excess: Relative to What? Hypertension, October 1, 2005; 46(4): 643 - 644. [Full Text] [PDF]
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S. J. Duffy, E. S. Biegelsen, R. T. Eberhardt, D. F. Kahn, B. A. Kingwell, and J. A. Vita Low-Renin Hypertension With Relative Aldosterone Excess Is Associated With Impaired NO-Mediated Vasodilation Hypertension, October 1, 2005; 46(4): 707 - 713. [Abstract] [Full Text] [PDF]
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W. B. White, B. Pitt, R. A. Preston, and V. Hanes Antihypertensive Effects of Drospirenone With 17{beta}-Estradiol, a Novel Hormone Treatment in Postmenopausal Women With Stage 1 Hypertension Circulation, September 27, 2005; 112(13): 1979 - 1984. [Abstract] [Full Text] [PDF]
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C. Saha, G. J. Eckert, W. T. Ambrosius, T.-Y. Chun, M. A. Wagner, Q. Zhao, and J. H. Pratt Improvement in Blood Pressure With Inhibition of the Epithelial Sodium Channel in Blacks With Hypertension Hypertension, September 1, 2005; 46(3): 481 - 487. [Abstract] [Full Text] [PDF]
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D. G. Warnock and P. D. Bell Improvement of Blood Pressure With Inhibition of the Epithelial Sodium Channel in Blacks With Hypertension Hypertension, September 1, 2005; 46(3): 469 - 470. [Full Text] [PDF]
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J. Ma, F. Albornoz, C. Yu, D. W. Byrne, D. E. Vaughan, and N. J. Brown Differing Effects of Mineralocorticoid Receptor-Dependent and -Independent Potassium-Sparing Diuretics on Fibrinolytic Balance Hypertension, August 1, 2005; 46(2): 313 - 320. [Abstract] [Full Text] [PDF]
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 D. Fraccarollo, P. Galuppo, I. Schmidt, G. Ertl, and J. Bauersachs Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction Cardiovasc Res, July 1, 2005; 67(1): 97 - 105. [Abstract] [Full Text] [PDF]
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 J. Ribstein, G. Du Cailar, P. Fesler, and A. Mimran Relative Glomerular Hyperfiltration in Primary Aldosteronism J. Am. Soc. Nephrol., May 1, 2005; 16(5): 1320 - 1325. [Abstract] [Full Text] [PDF]
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 A D Struthers Pathophysiology of heart failure following myocardial infarction Heart, May 1, 2005; 91(suppl_2): ii14 - ii16. [Abstract] [Full Text] [PDF]
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 P. Agostoni, A. Magini, D. Andreini, M. Contini, A. Apostolo, M. Bussotti, G. Cattadori, and P. Palermo Spironolactone improves lung diffusion in chronic heart failure Eur. Heart J., January 2, 2005; 26(2): 159 - 164. [Abstract] [Full Text] [PDF]
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D. R. Morgan, L. J. Dixon, C. G. Hanratty, S. M.T. Hughes, W. J. Leahey, K. P. Rooney, G. D. Johnston, and G. E. McVeigh Impaired endothelium-dependent and -independent vasodilation in elderly patients with chronic heart failure Eur J Heart Fail, December 1, 2004; 6(7): 901 - 908. [Abstract] [Full Text] [PDF]
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J. A.S. Muldowney III, S. N. Davis, D. E. Vaughan, and N. J. Brown NO Synthase Inhibition Increases Aldosterone in Humans Hypertension, November 1, 2004; 44(5): 739 - 745. [Abstract] [Full Text] [PDF]
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A. D Struthers Aldosterone blockade in cardiovascular disease Heart, October 1, 2004; 90(10): 1229 - 1234. [Full Text] [PDF]
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B. Pitt A New HOPE for Aldosterone Blockade? Circulation, September 28, 2004; 110(13): 1714 - 1716. [Full Text] [PDF]
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A. Garnier, J. K. Bendall, S. Fuchs, B. Escoubet, F. Rochais, J. Hoerter, J. Nehme, M.-L. Ambroisine, N. De Angelis, G. Morineau, et al. Cardiac Specific Increase in Aldosterone Production Induces Coronary Dysfunction in Aldosterone Synthase-Transgenic Mice Circulation, September 28, 2004; 110(13): 1819 - 1825. [Abstract] [Full Text] [PDF]
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A. D. Struthers The clinical implications of aldosterone escape in congestive heart failure Eur J Heart Fail, August 1, 2004; 6(5): 539 - 545. [Abstract] [Full Text] [PDF]
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B. Pitt Generic drugs in cardiology: will they reduce health care costs? J. Am. Coll. Cardiol., July 7, 2004; 44(1): 10 - 13. [Abstract] [Full Text] [PDF]
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S. J. Moat, S. N. Doshi, D. Lang, I. F. W. McDowell, M. J. Lewis, and J. Goodfellow Treatment of coronary heart disease with folic acid: is there a future? Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H1 - H7. [Full Text] [PDF]
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J E Macdonald, N Kennedy, and A D Struthers 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, July 1, 2004; 90(7): 765 - 770. [Abstract] [Full Text] [PDF]
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M. K. Nishizaka, M. A. Zaman, S. A. Green, K. Y. Renfroe, and D. A. Calhoun Impaired Endothelium-Dependent Flow-Mediated Vasodilation in Hypertensive Subjects With Hyperaldosteronism Circulation, June 15, 2004; 109(23): 2857 - 2861. [Abstract] [Full Text] [PDF]
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J. S. Sim, C. Farquharson, and A. D Struthers Tonic levels of angiotensin II reduce tonic levels of vascular nitric oxide even in salt-replete man Journal of Renin-Angiotensin-Aldosterone System, June 1, 2004; 5(2): 84 - 88. [Abstract] [PDF]
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S. Keidar, M. Kaplan, E. Pavlotzky, R. Coleman, T. Hayek, S. Hamoud, and M. Aviram 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, May 11, 2004; 109(18): 2213 - 2220. [Abstract] [Full Text] [PDF]
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E. L. Schiffrin The Many Targets of Aldosterone Hypertension, May 1, 2004; 43(5): 938 - 940. [Full Text] [PDF]
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J. Fletcher, A. N. Buch, H. C. Routledge, S. Chowdhary, J. H. Coote, and J. N. Townend Acute aldosterone antagonism improves cardiac vagal control in humans J. Am. Coll. Cardiol., April 7, 2004; 43(7): 1270 - 1275. [Abstract] [Full Text] [PDF]
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F. K Shieh, E. Kotlyar, and F. Sam Aldosterone and cardiovascular remodelling: focus on myocardial failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1): 3 - 13. [Abstract] [PDF]
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A. D Struthers Aldosterone blockade in heart failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1_suppl): S23 - S27. [Abstract] [PDF]
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K. Swedberg Conclusions on the management of heart failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1_suppl): S34 - S36. [Abstract] [PDF]
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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]
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E. M. Oestreicher, D. Martinez-Vasquez, J. R. Stone, L. Jonasson, W. Roubsanthisuk, K. Mukasa, and G. K. Adler Aldosterone and Not Plasminogen Activator Inhibitor-1 Is a Critical Mediator of Early Angiotensin II/NG-Nitro-l-Arginine Methyl Ester-Induced Myocardial Injury Circulation, November 18, 2003; 108(20): 2517 - 2523. [Abstract] [Full Text] [PDF]
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R. A. Ahokas, K. J. Warrington, I. C. Gerling, Y. Sun, L. A. Wodi, P. A. Herring, L. Lu, S. K. Bhattacharya, A. E. Postlethwaite, and K. T. Weber Aldosteronism and Peripheral Blood Mononuclear Cell Activation: A Neuroendocrine-Immune Interface Circ. Res., November 14, 2003; 93 (10): e124 - e135. [Abstract] [Full Text] [PDF]
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D. Fraccarollo, P. Galuppo, S. Hildemann, M. Christ, G. Ertl, and J. Bauersachs 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., November 5, 2003; 42(9): 1666 - 1673. [Abstract] [Full Text] [PDF]
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 M. Epstein Aldosterone receptor blockade and the role of eplerenone: evolving perspectives Nephrol. Dial. Transplant., October 1, 2003; 18(10): 1984 - 1992. [Full Text] [PDF]
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K. H Chee, K. Amudha, N. A Hussain, H. K Haizal, A.-M. J Choy, and C. C Lang Combination of drugs acting on the natriuretic system and the renin-angiotensin system in heart failure Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 140 - 148. [Abstract] [PDF]
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K. T Weber, Yao Sun, L. A Wodi, A. Munir, E. Jahangir, R. A Ahokas, I. C Gerling, A. E Postlethwaite, and K. J Warrington Toward a broader understanding of aldosterone in congestive heart failure Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 155 - 163. [Abstract] [PDF]
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B. Pitt, C. T Stier Jr, and S. Rajagopalan Mineralocorticoid receptor blockade: new insights into the mechanism of action in patients with cardiovascular disease Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 164 - 168. [Abstract] [PDF]
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A. F. Hernandez and C. M. O'Connor Sparing a little may save a lot: Lessons from the Studies of Left Ventricular Dysfunction (SOLVD) J. Am. Coll. Cardiol., August 20, 2003; 42(4): 709 - 711. [Full Text] [PDF]
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P. N. Chander, R. Rocha, J. Ranaudo, G. Singh, A. Zuckerman, and C. T. Stier Jr. Aldosterone Plays a Pivotal Role in the Pathogenesis of Thrombotic Microangiopathy in SHRSP J. Am. Soc. Nephrol., August 1, 2003; 14(8): 1990 - 1997. [Abstract] [Full Text] [PDF]
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Q. Pu, M. F. Neves, A. Virdis, R. M. Touyz, and E. L. Schiffrin Endothelin Antagonism on Aldosterone-Induced Oxidative Stress and Vascular Remodeling Hypertension, July 1, 2003; 42(1): 49 - 55. [Abstract] [Full Text] [PDF]
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A. Schafer, D. Fraccarollo, S. K Hildemann, P. Tas, G. Ertl, and J. Bauersachs Addition of the selective aldosterone receptor antagonist eplerenone to ACE inhibition in heart failure: effect on endothelial dysfunction Cardiovasc Res, June 1, 2003; 58(3): 655 - 662. [Abstract] [Full Text] [PDF]
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N. J. Brown Eplerenone: Cardiovascular Protection Circulation, May 20, 2003; 107(19): 2512 - 2518. [Abstract] [Full Text] [PDF]
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T.-Y. Chun, L. J. Bloem, and J. H. Pratt Aldosterone Inhibits Inducible Nitric Oxide Synthase in Neonatal Rat Cardiomyocytes Endocrinology, May 1, 2003; 144(5): 1712 - 1717. [Abstract] [Full Text] [PDF]
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 B. Pitt, W. Remme, F. Zannad, J. Neaton, F. Martinez, B. Roniker, R. Bittman, S. Hurley, J. Kleiman, M. Gatlin, et al. Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction N. Engl. J. Med., April 3, 2003; 348(14): 1309 - 1321. [Abstract] [Full Text] [PDF]
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 D. L. Brutsaert Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity Physiol Rev, January 1, 2003; 83(1): 59 - 115. [Abstract] [Full Text] [PDF]
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J. G. F. Bronzwaer, C. Heymes, C. A. Visser, and W. J. Paulus Myocardial fibrosis blunts nitric oxide synthase-related preload reserve in human dilated cardiomyopathy Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H10 - H16. [Abstract] [Full Text] [PDF]
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C A J Farquharson and A D Struthers Increasing plasma potassium with amiloride shortens the QT interval and reduces ventricular extrasystoles but does not change endothelial function or heart rate variability in chronic heart failure Heart, December 1, 2002; 88(5): 475 - 480. [Abstract] [Full Text] [PDF]
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M. F. Rousseau, O. Gurne, D. Duprez, W. Van Mieghem, A. Robert, S. Ahn, L. Galanti, J.-M. Ketelslegers, and Belgian RALES Investigators Beneficial neurohormonal profile of spironolactone in severe congestive heart failure: Results from the RALES neurohormonal substudy J. Am. Coll. Cardiol., November 6, 2002; 40(9): 1596 - 1601. [Abstract] [Full Text] [PDF]
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 Y. Sun, J. Zhang, L. Lu, S. S. Chen, M. T. Quinn, and K. T. Weber Aldosterone-Induced Inflammation in the Rat Heart : Role of Oxidative Stress Am. J. Pathol., November 1, 2002; 161(5): 1773 - 1781. [Abstract] [Full Text] [PDF]
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A. Virdis, M. F. Neves, F. Amiri, E. Viel, R. M. Touyz, and E. L. Schiffrin Spironolactone Improves Angiotensin-Induced Vascular Changes and Oxidative Stress Hypertension, October 1, 2002; 40(4): 504 - 510. [Abstract] [Full Text] [PDF]
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J. Davies and A. Struthers Review: The potential benefits of aldosterone antagonism in Type 2 diabetes mellitus Journal of Renin-Angiotensin-Aldosterone System, September 1, 2002; 3(3): 150 - 155. [Abstract] [PDF]
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M. Cicoira, L. Zanolla, A. Rossi, G. Golia, L. Franceschini, G. Brighetti, P. Marino, and P. Zardini Long-term, dose-dependent effects of spironolactone on left ventricular function and exercise tolerance in patients with chronic heart failure J. Am. Coll. Cardiol., July 17, 2002; 40(2): 304 - 310. [Abstract] [Full Text] [PDF]
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C. A.J. Farquharson, R. Butler, A. Hill, J. J.F. Belch, and A. D. Struthers Allopurinol Improves Endothelial Dysfunction in Chronic Heart Failure Circulation, July 9, 2002; 106(2): 221 - 226. [Abstract] [Full Text] [PDF]
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C. A. J. Farquharson and A. D. Struthers Gradual reactivation over time of vascular tissue angiotensin I to angiotensin II conversion during chronic lisinopril therapy in chronic heart failure J. Am. Coll. Cardiol., March 6, 2002; 39(5): 767 - 775. [Abstract] [Full Text] [PDF]
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P. Sawathiparnich, S. Kumar, D. E. Vaughan, and N. J. Brown Spironolactone Abolishes the Relationship between Aldosterone and Plasminogen Activator Inhibitor-1 in Humans J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 448 - 452. [Abstract] [Full Text] [PDF]
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J. Bauersachs, M. Heck, D. Fraccarollo, S. K. Hildemann, G. Ertl, M. Wehling, and M. Christ 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., January 16, 2002; 39(2): 351 - 358. [Abstract] [Full Text] [PDF]
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K. T. Weber Aldosterone in Congestive Heart Failure N. Engl. J. Med., December 6, 2001; 345(23): 1689 - 1697. [Full Text] [PDF]
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A. D Struthers Review: Aldosterone-induced vasculopathy: a new reversible cause of cardiac death Journal of Renin-Angiotensin-Aldosterone System, December 1, 2001; 2(4): 211 - 214. [PDF]
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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]
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J. B. Park and E. L. Schiffrin ETA Receptor Antagonist Prevents Blood Pressure Elevation and Vascular Remodeling in Aldosterone-Infused Rats Hypertension, June 1, 2001; 37(6): 1444 - 1449. [Abstract] [Full Text] [PDF]
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T. Quaschning, F. Ruschitzka, S. Shaw, and T. F. Luscher Aldosterone Receptor Antagonism Normalizes Vascular Function in Liquorice-Induced Hypertension Hypertension, February 1, 2001; 37(2): 801 - 805. [Abstract] [Full Text] [PDF]
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 M. Epstein Aldosterone as a determinant of cardiovascular and renal dysfunction J R Soc Med, January 8, 2001; 94(8): 378 - 383. [Full Text] [PDF]
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