(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
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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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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