Abstract
Aldosterone is known to play a role in the pathophysiology of some cardiovascular diseases. However, previous studies on aldosterone infusion have been mostly performed in animals receiving sodium loading and uninephrectomy, and thus the cardiac action of aldosterone alone remains to be fully clarified. The present study was undertaken to investigate the direct cardiac action of aldosterone infusion alone in rats not subjected to salt loading and uninephrectomy. Aldosterone (0.75 μg/h) was subcutaneously infused into rats via an osmotic minipump for 14 days. Aldosterone infusion, under a normal salt diet, induced only a slight increase in the blood pressure of normal rats throughout the infusion. However, aldosterone significantly induced cardiac hypertrophy, as shown by echocardiography and measurement of cardiomyocyte cross-sectional area. Furthermore, aldosterone caused not only cardiac interstitial macrophage infiltration but also cardiac focal inflammatory lesions, which were associated with an increase in cardiac monocyte chemoattractant protein-1 (MCP-1) and osteopontin mRNA. The slight elevation of blood pressure by aldosterone infusion was completely prevented by tempol, the superoxide dismutase mimetic. However, tempol failed to suppress cardiac hypertrophy, the formation of inflammatory lesions, and upregulation of cardiac MCP-1 and osteopontin by aldosterone, while N-acetylcysteine could inhibit all of them. Our data provide evidence that aldosterone alone can induce cardiac hypertrophy and severe inflammatory response in the heart, independently of blood pressure, even in the absence of salt loading or nephrectomy. Aldosterone seems to induce cardiac inflammation and gene expression via oxidative stress that is inhibited by N-acetylcysteine but not by tempol.
References
Sato A, Hayashi M, Saruta T : Relative long-term effects of spironolactone in conjunction with an angiotensin-converting enzyme inhibitor on left ventricular mass and diastolic function in patients with essential hypertension. Hypertens Res 2002; 25: 837–842.
Sato A, Saruta T : Aldosterone-induced organ damage: plasma aldosterone level and inappropriate salt status. Hypertens Res 2004; 27: 303–310.
Iwashima Y, Horio T, Kuroda S, Takishita S, Kawano Y : Influence of plasma aldosterone on left ventricular geometry and diastolic function in treated essential hypertension. Hypertens Res 2002; 25: 49–56.
Gerling IC, Sun Y, Ahokas RA, et al: Aldosteronism: an immunostimulatory state precedes proinflammatory/fibrogenic cardiac phenotype. Am J Physiol Heart Circ Physiol 2003; 285: H813–H821.
Pitt B, Remme W, Zannad F, et al: Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348: 1309–1321.
Pitt B, Zannad F, Remme WJ, et al: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341: 709–717.
Rocha R, Martin-Berger CL, Yang P, Scherrer R, Delyani J, McMahon E : Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart. Endocrinology 2002; 143: 4828–4836.
Rocha R, Rudolph AE, Frierdich GE, et al: Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol 2002; 283: H1802–H1810.
Sun Y, Zhang J, Lu L, Chen SS, Quinn MT, Weber KT : Aldosterone-induced inflammation in the rat heart: role of oxidative stress. Am J Pathol 2002; 161: 1773–1781.
Weber KT : Aldosterone in congestive heart failure. N Engl J Med 2001; 345: 1689–1697.
Weber KT, Sun Y, Guarda E : Structural remodeling in hypertensive heart disease and the role of hormones. Hypertension 1994; 23: 869–877.
Rossi GP, Di Bello V, Ganzaroli C, et al: Excess aldosterone is associated with alterations of myocardial texture in primary aldosteronism. Hypertension 2002; 40: 23–27.
Rossi GP, Sacchetto A, Visentin P, et al: Changes in left ventricular anatomy and function in hypertension and primary aldosteronism. Hypertension 1996; 27: 1039–1045.
Ganguly A : Primary aldosteronism. N Engl J Med 1998; 339: 1828–1834.
Park JB, Schiffrin EL : Cardiac and vascular fibrosis and hypertrophy in aldosterone-infused rats: role of endothelin-1. Am J Hypertens 2002; 15: 164–169.
Chatterjee PK, Cuzzocrea S, Brown PA, et al: Tempol, a membrane-permeable radical scavenger, reduces oxidant stress-mediated renal dysfunction and injury in the rat. Kidney Int 2000; 58: 658–673.
Nishiyama A, Yao L, Nagai Y, et al: Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/salt-induced hypertensive rats. Hypertension 2004; 43: 841–848.
Beswick RA, Zhang H, Marable D, Catravas JD, Hill WD, Webb RCZ : Long-term antioxidant administration attenuates mineralocorticoid hypertension and renal inflammatory response. Hypertension 2001; 37: 781–786.
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.
Kim S, Izumi Y, Izumiya Y, Zhan Y, Taniguchi M, Iwao H : Beneficial effects of combined blockade of ACE and AT1 receptor on intimal hyperplasia in balloon-injured rat artery. Arterioscler Thromb Vasc Biol 2002; 22: 1299–1304.
Izumiya Y, Kim S, Izumi Y, et al: Apoptosis signal-regulating kinase 1 plays a pivotal role in angiotensin II-induced cardiac hypertrophy and remodeling. Circ Res 2003; 93: 874–883.
Izumi Y, Kim S, Zhan Y, Namba M, Yasumoto H, Iwao H : Important role of angiotensin II-mediated c-Jun NH2-terminal kinase activation in cardiac hypertrophy in hypertensive rats. Hypertension 2000; 36: 511–516.
Kim S, Yoshiyama M, Izumi Y, et al: Effects of combination of ACE inhibitor and angiotensin receptor blocker on cardiac remodeling, cardiac function, and survival in rat heart failure. Circulation 2001; 103: 148–154.
Selye H : The general adaptation syndrome and the diseases of adaptation. J Clin Endocrinol Metab 1946; 6: 117–230.
Brilla CG, Weber KT : Reactive and reparative myocardial fibrosis in arterial hypertension in the rat. Cardiovasc Res 1992; 26: 671–677.
Robert V, Silvestre JS, Charlemagne D, et al: Biological determinants of aldosterone-induced cardiac fibrosis in rats. Hypertension 1995; 26: 971–978.
Brilla CG, Weber KT : Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med 1992; 120: 893–901.
Sun Y, Ramires FJ, Weber KT : Fibrosis of atria and great vessels in response to angiotensin II or aldosterone infusion. Cardiovasc Res 1997; 35: 138–147.
Campbell SE, Janicki JS, Weber KT : Temporal differences in fibroblast proliferation and phenotype expression in response to chronic administration of angiotensin II or aldosterone. J Mol Cell Cardiol 1995; 27: 1545–1560.
Ahokas RA, Warrington KJ, Gerling IC, et al: Aldosteronism and peripheral blood mononuclear cell activation: a neuroendocrine-immune interface. Circ Res 2003; 93: e124–e135.
Zafarullah M, Li WQ, Sylvester J, Ahmad M : Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci 2003; 60: 6–20.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yoshida, K., Kim-Mitsuyama, S., Wake, R. et al. Excess Aldosterone under Normal Salt Diet Induces Cardiac Hypertrophy and Infiltration via Oxidative Stress. Hypertens Res 28, 447–455 (2005). https://doi.org/10.1291/hypres.28.447
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1291/hypres.28.447
Keywords
- aldosterone
- angiotensin II
- cardiac hypertrophy
- oxidative stress
- inflammation
This article is cited by
-
Diagnostic accuracy of using multiple cytokines to predict aldosterone-producing adenoma
Scientific Reports (2023)
-
Myocardial pathology induced by aldosterone is dependent on non-canonical activities of G protein-coupled receptor kinases
Nature Communications (2016)
-
Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis
Nature Reviews Nephrology (2013)
-
Remote preconditioning in normal and hypertrophic rat hearts
Journal of Cardiothoracic Surgery (2011)
