Published online before print March 8, 2004, doi: 10.1161/01.HYP.0000123573.60340.9b
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2004;43:938.)
© 2004 American Heart Association, Inc.
Editorial Commentaries |
The Many Targets of Aldosterone
From the Canadian Institutes of Health Research Multidisciplinary Research Group on Hypertension and Hypertension Clinic, Clinical Research Institute of Montréal, Québec, Canada.
Correspondence to Ernesto L. Schiffrin, MD, PhD, FRCPC, Clinical Research Institute of Montreal, 110 Pine Avenue, West Montreal, Quebec, Canada H2W 1R7. E-mail ernesto.schiffrin{at}ircm.qc.ca
In the current issue of Hypertension, Oberleithner et al1 demonstrate a new effect of aldosterone acting via mineralocorticoid receptors to stimulate water entry into human endothelial cells. Using atomic force microscopy, these authors show that cultured human umbilical vein endothelial cells respond to aldosterone with sodium and water entry (they swell) and this can be blocked by a mineralocorticoid receptor blocker (spironolactone). Swollen aldosterone-treated endothelial cells shrink when micromolar concentrations of amiloride are applied, concentrations at which amiloride does not inhibit the sodium-proton exchanger. The authors report they already showed that cariporide, a selective inhibitor of the sodium-proton exchanger, does not affect aldosterone-induced endothelial cell swelling.1 Thus, they suggest that amiloride inhibits a sodium channel similar to the apical epithelial sodium channel in the distal nephron. The authors conclude that sodium channels are induced by genomic effects of aldosterone, which result in sodium influx and cell depolarization, creating an electrochemical gradient that leads to chloride and water accumulation and cell swelling. Amiloride, by blocking the sodium channels, hyperpolarizes the cell, leading to chloride efflux followed by efflux of water and cell shrinkage. Whether this interpretation is correct remains to be proven. The authors propose that endothelial cell swelling followed by sodium influx also leads to activation of the sodium/potassium ATPase and potassium influx. They suggest that, considering the huge surface of endothelium, aldosterone may reduce serum concentrations of potassium not only by its renal action but also mediated by inducing potassium entry into endothelial cells as a result of sodium/potassium ATPase activation. Furthermore, amiloride could have opposite effects on the hypokalemia of patients with hyperaldosteronism by leading to rapid potassium shifts from inside swollen endothelial cells. These conclusions remain to be supported by further appropriate animal or clinical experimentation. However, this study adds to the increasing literature that shows that aldosterone exerts important physiologically and/or pathophysiologically relevant effects on the cardiovascular system and on different organs, including the brain, in contrast to the notion that mineralocorticoids are only involved in body electrolyte and water homeostasis mediated by the kidney, which has been accepted for more than half a century.2
These same authors also demonstrated by applying atomic force microscopy to endothelial cells that aldosterone rapidly (<10 minutes) induced an increase of the cell nucleus that could reach 15% to 28% of total cell volume and disappeared within 30 minutes.3 Additionally, they showed that 2 minutes after aldosterone injection into Xenopus laevis oocytes intracellular receptors bound to nuclear pores on the nuclear membrane, which then translocated into the nucleus. Fifteen minutes later macromolecules that resemble ribonucleoproteins and which could carry the aldosterone-induced mRNA to ribosomes were visualized in the central channels of the nuclear pores. They postulated that aldosterone-induced nuclear swelling was a rapid genomic effect as receptors translocated from the cytoplasm into the nucleus and gene transcription followed, with the return of normal nuclear volume when mRNA was exported into the cytoplasm. The authors concluded that responses to aldosterone could no longer be divided into acute nongenomic (<10 minutes) and sustained genomic (>10 minutes) effects, because rapid genomic effects could be demonstrated.3 They further hypothesized that this phenomenon that resulted in swelling of endothelial cells as described in the current study1 could affect resistance to blood flow in small arteries.
Aldosterone has been shown to be produced in the heart4,5 and blood vessels,6,7 although it is still not established whether the concentrations achieved are high enough to exert local effects.8 Perhaps more importantly, cardiac and vascular mineralocorticoid receptors have also been demonstrated.9 Aldosterone has been implicated in the induction of fibrosis in heart, blood vessels, and the kidney, particularly in the presence of high salt.10–13 In addition, actions that are usually attributed to direct effects of angiotensin II, such as vascular remodeling, endothelial dysfunction via increased oxidative stress, and inflammation of the vascular wall and heart, may in fact be mediated at least in part by aldosterone.14 An inflammatory cardiovascular and renal response to mineralocorticoids and particularly to aldosterone has been clearly established15–18 and may occur more easily in the presence of high salt, which seems to sensitize the cardiovascular system to nefarious effects of aldosterone. Inflammatory responses have increasingly been associated with the mechanisms involved in the pathophysiology of cardiovascular disease.19 The vascular and cardiac inflammatory response includes upregulation of inflammatory mediators such as NF
B and AP-1, adhesion molecules such as vascular cell adhesion molecule-1 and intracellular adhesion molecule-1, and endothelin-1.20 It would be of interest to determine if these mechanisms are activated by endothelial cell swelling. The phenomena revealed by Oberleithner et al1 could then also be implicated not only in regulation of body water and electrolytes, but also in some of the newer pathophysiological effects attributed to aldosterone that participate in cardiovascular disease.
The knowledge that aldosterone may act on the endothelium is not new. It has been suggested that aldosterone may act on endothelial cells to impair endothelial function, which could occur in response to stimulation of oxidant stress by aldosterone.17,21,22 Recently, and in contrast to previous studies, other investigators have demonstrated that rather than a deleterious effect in response to aldosterone, a beneficial action can be observed on endothelial function via phosphatidylinositol 3-kinase-dependent activation of nitric oxide synthase.23 Mineralocorticoids including aldosterone stimulate the production of endothelin-1 in the kidney, vasculature, and heart.11,12,20,24–27 How these effects interplay in the vasculature and the heart to result in the actions of aldosterone during normal body homeostasis and in pathological conditions such as essential hypertension or heart failure is unclear.
A role of aldosterone in essential hypertension has been suggested for many years,28 and recent data with the new mineralocorticoid receptor blocker eplerenone29,30 seems to provide further support to this hypothesis. The realization that hyperaldosteronism may be a relatively frequent mechanism of elevated blood pressure and the search for the more numerous cases of primary aldosteronism among hypertensive patients31,32add to the interest in both the cardiovascular effects of mineralocorticoids and the potential for new approaches to therapeutic intervention in hypertension. In heart failure, blockade of mineralocorticoid receptors not only improvea endothelial function21 but also reduced events in the Randomized Aldactone Evaluation Study trial33and post myocardial infarction in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study trial.34 The rather extraordinary saga of aldosterone does not end with these very significant therapeutic findings. The interest in this effector of the renin-angiotensin system may go further. The finding that there are mineralocorticoid receptors in the brain that result in stimulation of the sympathetic nervous system and may induce blood pressure elevation as well as inflammatory responses further complicates and enriches our understanding of the pleiotropic actions of aldosterone.35,36
The study by Oberleithner et al1 may be one of many that will in the near future add to the complexity of our understanding of the multiple targets of aldosterone. Increased mechanistic knowledge of this critical mediator and its many targets will contribute to our ability to act therapeutically to the benefit of patients with cardiovascular disease, including hypertension, ischemic heart disease, stroke, heart failure, and renal disease.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
(Hypertension. 2004;43:938–940.)
References
1. Oberleithner H, Ludwig T, Riethmüller C, Hillebrand U, Altermann L, Schäffer C, Shahin V. Human endothelium, target for aldosterone. Hypertension. 2004; 43: 952–956.
2. Kuhlman D, Ragan C, Ferrebee JW, Atchley DW, Loeb RF. Toxic effects of deoxycorticosterone esters in dogs. Science. 1939; 90: 496–497.
3. Oberleithner H, Reinhardt J, Schillers H, Pagel P, Schneider SW. Aldosterone and nuclear volume cycling. Cell Physiol Biochem. 2000; 10: 429–434.[CrossRef][Medline] [Order article via Infotrieve]
4. Silvestre JS, Heymes C, Oubenaissa A, Robert V, Aupetit-Faisant B, Carayon A, Swynghedauw B, Delcayre C. Activation of cardiac aldosterone production in rat myocardial infarction: effect of angiotensin II receptor blockade and role in cardiac fibrosis. Circulation. 1999; 99: 2694–2701.
5. Delcayre C, Silvestre JS, Garnier A, Oubenaissa A, Cailmail S, Tatara E, Swynghedauw B, Robert V. Cardiac aldosterone production and ventricular remodeling. Kidney Int. 2000; 57: 1346–1351.[CrossRef][Medline] [Order article via Infotrieve]
6. Takeda Y, Miyamori I, Yoneda T, Iki K, Hatakeyama H, Blair IA, Hsieh F-Y, Takeda R. Production of aldosterone in isolated rat blood vessels. Hypertension. 1995; 25: 170–173.
7. Hatakeyama H, Miyamori I, Fujita T, Takeda Y, Takeda R, Yamamoto H. Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells. J Biol Chem. 1994; 269: 24316–24320.
8. Gomez-Sanchez CE, Gomez-Sanchez EP. Cardiac steroidogenesis-new sites of synthesis, or much ado about nothing? J Clin Endocrinol Metab. 2001; 86: 5118–5120.
9. Funder JW, Pearce PT, Smith R, Campbell J. Vascular type I aldosterone binding sites are physiological mineralocorticoid receptors. Endocrinology. 1989; 125: 2224–2226.
10. Weber KT, Sun Y, Guarda E. Structural remodeling in hypertensive heart disease and the role of hormones. Hypertension. 1994; 23: 869–877.
11. Park JB, Schiffrin EL. ETA receptor antagonist prevents blood pressure elevation and vascular remodeling in aldosterone-infused rats. Hypertension. 2001; 37: 1444–1449.
12. Park JB, Schiffrin EL. Cardiac and vascular fibrosis and hypertrophy in aldosterone-infused rats: Role of endothelin-1. Am J Hypert. 2002; 15: 164–169.[CrossRef][Medline] [Order article via Infotrieve]
13. Blasi ER, Rocha R, Rudolph AE, Blomme EAG, Polly ML, McMahon EG. Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats. Kidney Int. 2003; 63: 1791–1800.[CrossRef][Medline] [Order article via Infotrieve]
14. 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.
15. Rocha R, Chander PN, Zuckerman A, Stier CT, Jr. Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats. Hypertension. 1999; 33: 232–237.
16. Rocha R, Martin-Berger CL, Yang PC, Scherrer R, Delyani J, McMahon E. Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart. Endocrinol. 2002; 143: 4828–4836.
17. Pu Q, Neves MF, Virdis A, Touyz RM, Schiffrin EL. Endothelin antagonism on aldosterone-induced oxidative stress and vascular remodeling. Hypertension. 2003; 42: 49–55.
18. Tostes RCA, Touyz RM, He G, Chen X, Schiffrin EL. Contribution of endothelin-1 to renal activator protein-1 activation and macrophage infiltration in aldosterone-induced hypertension. Clin Sci. 2002; 103: 25S–30S.[Medline] [Order article via Infotrieve]
19. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002; 105: 1135–1143.
20. Ammarguellat FZ, Gannon PO, Amiri F, Schiffrin EL. Fibrosis, matrix metalloproteinases, and inflammation in the heart of DOCA-salt hypertensive rats: Role of ETA receptors. Hypertension. 2002; 39: 679–684.
21. 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.
22. Farquharson CAJ, Struthers AD. Aldosterone induces acute endothelial dysfunction in vivo in humans: evidence for an aldosterone-induced vasculopathy. Clin Sci. 2002; 103: 425–431.[Medline] [Order article via Infotrieve]
23. Liu SL, Schmuck S, Chorazcyzewski JZ, Gros R, Feldman RD. Aldosterone regulates vascular reactivity - Short-term effects mediated by phosphatidylinositol 3-kinase-dependent nitric oxide synthase activation. Circulation. 2003; 108: 2400–2406.
24. Ammarguellat F, Larouche I, Schiffrin EL. Myocardial fibrosis in DOCA-salt hypertensive rats - Effect of endothelin ETA receptor antagonism. Circulation. 2001; 103: 319–324.
25. Deng LY, Day R, Schiffrin EL. Localization of sites of enhanced expression of endothelin-1 in the kidney of DOCA-salt hypertensive rats. J Am Soc Nephrol. 1996; 7: 1158–1164.[Abstract]
26. Larivière R, Day R, Schiffrin EL. Increased expression of endothelin-1 gene in blood vessels of deoxycorticosterone acetate-salt hypertensive rats. Hypertension. 1993; 21: 916–920.
27. Lariviere R, Deng LY, Day R, Sventek P, Thibault G, Schiffrin EL. Increased endothelin-1 gene expression in the endothelium of coronary arteries and endocardium in the DOCA-salt hypertensive rat. J Mol Cell Cardiol. 1995; 27: 2123–2131.[CrossRef][Medline] [Order article via Infotrieve]
28. Genest J, Lemieux G, Davignon A, Koiw E, Nowaczynski W, Steyermark P. Human arterial hypertension: A state of mild chronic hyperaldosteronism? Science. 1956; 123: 503–505.
29. Weinberger MH, Roniker B, Krause SL, Weiss RJ. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypert. 2002; 15: 709–716.[CrossRef][Medline] [Order article via Infotrieve]
30. Pitt B, Reichek N, Willenbrock R, Zannad F, Phillips RA, Roniker B, Kleiman J, Krause S, Burns D, Williams GH. Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy - The 4E-left ventricular hypertrophy study. Circulation. 2003; 108: 1831–1838.
31. Stowasser M. New perspectives on the role of aldosterone excess in cardiovascular disease. Clin Exp Pharmacol Physiol. 2001; 28: 783–791.[CrossRef][Medline] [Order article via Infotrieve]
32. Stowasser M. Primary aldosteronism: rare bird or common cause of secondary hypertension? Curr Hypertens Rep. 2001; 3: 230–239.[Medline] [Order article via Infotrieve]
33. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez, 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.
34. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M, Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309–1321.
35. Meijer OC, Van Acker SA, Sibug RM, Oitzl MS, Meijer OC, Rahmouni K, de Jong W. Brain mineralocorticoid receptors and centrally regulated functions. Kidney Int. 2000; 57: 1329–1336.[CrossRef][Medline] [Order article via Infotrieve]
36. Rahmouni K, Sibug RM, De Kloet ER, Barthelmebs M, Grima M, Imbs JL, De Jong W. Effects of brain mineralocorticoid receptor blockade on blood pressure and renal functions in DOCA-salt hypertension. Eur J Pharmacol. 2002; 436: 207–216.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  S. Shibata, M. Nagase, S. Yoshida, H. Kawachi, and T. Fujita Podocyte as the Target for Aldosterone: Roles of Oxidative Stress and Sgk1 Hypertension, February 1, 2007; 49(2): 355 - 364. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. L. Brooks, K. L. Freeman, and Y. Qi Time course of synergistic interaction between DOCA and salt on blood pressure: roles of vasopressin and hepatic osmoreceptors Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2006; 291(6): R1825 - R1834. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Rizzoni, S. Paiardi, L. Rodella, E. Porteri, C. De Ciuceis, R. Rezzani, G. E. M. Boari, F. Zani, M. Miclini, G. A. M. Tiberio, et al. Changes in Extracellular Matrix in Subcutaneous Small Resistance Arteries of Patients with Primary Aldosteronism J. Clin. Endocrinol. Metab., July 1, 2006; 91(7): 2638 - 2642. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Schiffrin Effects of Aldosterone on the Vasculature Hypertension, March 1, 2006; 47(3): 312 - 318. [Full Text] [PDF]
|
|
|
|
|
|
T. L. Pallone Microvascular Effects of Aldosterone and Angiotensin Type 2 Receptors Hypertension, May 1, 2005; 45(5): 845 - 846. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||