The Mechanisms of Actions of Aldosterone and its Antagonists in Cardiovascular Disease

Author(s): Panteleimon Pantelidis, Michail Sideris, Margus Viigimaa, Konstantinos Avranas, Pavlos Deligkaris, Ioanna Zografou, Dragan Lovic*.

Journal Name: Current Pharmaceutical Design

Volume 24 , Issue 46 , 2018


Abstract:

Background: Aldosterone, through its actions on Mineralcorticosteroid Receptors (MR), controls fluid and electrolyte balance, but also exerts various direct deleterious actions on the vasculature. A number of aldosterone antagonists have been manufactured to reverse these effects.

Objective: A comprehensive review of the underlying mechanisms of the actions of aldosterone and its antagonists in cardiovascular disease.

Method: The relevant studies indexed in PubMed, Scopus and Google Scholar databases, published from 2003 to May 2018 were identified and reported.

Results: Aldosterone binds to MR, activating them as intracellular transcription factors. Moreover, aldosterone, through its actions on MR, as well as on another not fully explored class of receptors, triggers several signaling pathways that produce rapid, non-genomic actions. In the vasculature, all these changes favor the establishment of inflammation and cardiovascular dysfunction, which, in turn, lead to or exacerbate various cardiovascular diseases. Mineralcorticosteroid Antagonists (MRA) are compounds that antagonize the action of aldosterone on MR. Spironolactone was the first steroidal MRA to be commercially used. It showed beneficial clinical results, but also a number of adverse effects. The next generation of steroidal MRA, exhibited lower potency but did not induce many of these adverse reactions, due to their high selectivity for MR. The third generation of MRA compromises the newly introduced non-steroidal MRA, which have a completely different chemical structure, they induce different and more drastic changes to MR, they are much more specific and currently under clinical trials.

Conclusion: New MRA, which block the aldosterone induced pathways in the vasculature, hold promising results for the treatment of cardiovascular disease.

Keywords: Aldosterone, mineralocorticoid antagonists, cardiovascular disease, spironolactone, eplerenone, non-steroidal MRAs, Steroidal MRAs.

[1]
Coghlan J, Tait JF. Aldosterone: History and introduction Textbook of nephro-endocrinology 2009; 309-27.
[2]
Williams GH. Aldosterone biosynthesis, regulation, and classical mechanism of action. Heart Fail Rev 2005; 10(1): 7-13.
[3]
Arai K, Chrousos GP. Aldosterone Deficiency and Resistance. In:De Groot LJ, Chrousos G, Dungan K, et al., Eds. Endotext. South Dartmouth (MA): MDText.com, Inc 2000.
[4]
Markowitz M, Messineo F, Coplan NL. Aldosterone receptor antagonists in cardiovascular disease: A review of the recent literature and insight into potential future indications. Clin Cardiol 2012; 35(10): 605-9.
[5]
Gajjala PR, Sanati M, Jankowski J. Cellular and molecular mechanisms of chronic kidney disease with diabetes mellitus and cardiovascular diseases as its comorbidities. Front Immunol 2015; 6: 340.
[6]
Häggström M, Richfield D. Diagram of the pathways of human steroidogenesis. WikiJournal Med 2014; 1: 1-5.
[7]
Bollag WB. Regulation of aldosterone synthesis and secretion. Compr Physiol 2014; 4(3): 1017-55.
[8]
McKay L, Cidlowski J. Pharmacokinetics of Corticosteroids 6th ed. Holland-Frei Cancer Medicine. 2003.
[9]
DuPont JJ, Jaffe IZ. 30 years of the mineralocorticoid receptor: The role of the mineralocorticoid receptor in the vasculature. J Endocrinol 2017; 234(1): T67-82.
[10]
Wu F, Lin Y, Liu Q. The emerging role of aldosterone/mineralocorticoid receptors in the pathogenesis of erectile dysfunction. Endocrine 2018; 61(3): 372-82.
[11]
Beuschlein F. Regulation of aldosterone secretion: from physiology to disease. Eur J Endocrinol 2013; 168(6): R85-93.
[12]
Faulkner JL, Bruder-Nascimento T, Belin de Chantemèle EJ. The regulation of aldosterone secretion by leptin: implications in obesity-related cardiovascular disease. Curr Opin Nephrol Hypertens 2018; 27(2): 63-9.
[13]
Even SEL, Dulak-Lis MG, Touyz RM, Nguyen Dinh Cat A. Crosstalk between adipose tissue and blood vessels in cardiometabolic syndrome: implication of steroid hormone receptors (MR/GR). Horm Mol Biol Clin Investig 2014; 19(2): 89-101.
[14]
Tamargo J, Solini A, Ruilope LM. Comparison of agents that affect aldosterone action. Semin Nephrol 2014; 34(3): 285-306.
[15]
Nappi JM, Sieg A. Aldosterone and aldosterone receptor antagonists in patients with chronic heart failure. Vasc Health Risk Manag 2011; 7: 353-63.
[16]
Thomas W, Harvey BJ. Mechanisms underlying rapid aldosterone effects in the kidney. Annu Rev Physiol 2011; 73: 335-57.
[17]
Koenig JB, Jaffe IZ. Direct role for smooth muscle cell mineralocorticoid receptors in vascular remodeling: novel mechanisms and clinical implications. Curr Hypertens Rep 2014; 16(5): 427.
[18]
Verhovez AA, Williams T, Monticone S, et al. Genomic and Non-genomic Effects of Aldosterone. Curr Signal Transduct Ther 2012; 7: 132-41.
[19]
Boldyreff B, Wehling M. Non-genomic actions of aldosterone: mechanisms and consequences in kidney cells. Nephrol Dial Transplant 2003; 18(9): 1693-5.
[20]
Odermatt A, Kratschmar DV. Tissue-specific modulation of mineralocorticoid receptor function by 11β-hydroxysteroid dehydrogenases: An overview. Mol Cell Endocrinol 2012; 350(2): 168-86.
[21]
Funder JW. Aldosterone and mineralocorticoid receptors-physiology and pathophysiology. Int J Mol Sci 2017; 18(5): 1032.
[22]
Korah HE, Scholl UI. An update on familial hyperaldosteronism. Horm Metab Res 2015; 47(13): 941-6.
[23]
Ovaert P, Elliott J, Bernay F, Guillot E, Bardon T. Aldosterone receptor antagonists--how cardiovascular actions may explain their beneficial effects in heart failure. J Vet Pharmacol Ther 2010; 33(2): 109-17.
[24]
Lang F, Ritz E, Alesutan I, Voelkl J. Impact of aldosterone on osteoinductive signaling and vascular calcification. Nephron, Physiol 2014; 128(1-2): 40-5.
[25]
Tamargo M, Tamargo J. Future drug discovery in renin-angiotensin-aldosterone system intervention. Expert Opin Drug Discov 2017; 12(8): 827-48.
[26]
Fischer AK, von Rosenstiel P, Fuchs E, Goula D, Almeida OF, Czéh B. The prototypic mineralocorticoid receptor agonist aldosterone influences neurogenesis in the dentate gyrus of the adrenalectomized rat. Brain Res 2002; 947(2): 290-3.
[27]
Fujii H. Association between parathyroid hormone and cardiovascular disease. Ther Apher Dial 2018; 22(3): 236-41.
[28]
Luther JM. Effects of aldosterone on insulin sensitivity and secretion. Steroids 2014; 91: 54-60.
[29]
Briet M, Schiffrin EL. The role of aldosterone in the metabolic syndrome. Curr Hypertens Rep 2011; 13(2): 163-72.
[30]
Haller H, Bertram A, Stahl K, Menne J. Finerenone: A New Mineralocorticoid Receptor Antagonist Without Hyperkalemia: An Opportunity in Patients with CKD? Curr Hypertens Rep 2016; 18(5): 41.
[31]
Neves MF, Cunha AR, Cunha MR, Gismondi RA, Oigman W. The role of renin-angiotensin-aldosterone system and its new components in arterial stiffness and vascular aging. High Blood Press Cardiovasc Prev 2018; 25(2): 137-45.
[32]
Wehling M. Rapid actions of aldosterone revisited: Receptors in the limelight. J Steroid Biochem Mol Biol 2018; 176: 94-8.
[33]
Queisser N, Schupp N. Aldosterone, oxidative stress, and NF-κB activation in hypertension-related cardiovascular and renal diseases. Free Radic Biol Med 2012; 53(2): 314-27.
[34]
Kolodziejczyk P, Gromotowicz-Poplawska A, Aleksiejczuk M, Chabielska E, Tutka P, Miltyk W. New sides of aldosterone action in cardiovascular system as potential targets for therapeutic intervention. Curr Drug Targets 2018; 19(16): 1968-79.
[35]
Epstein M, Calhoun DA. Aldosterone blockers (mineralocorticoid receptor antagonism) and potassium-sparing diuretics. J Clin Hypertens (Greenwich) 2011; 13(9): 644-8.
[36]
Kolkhof P, Bärfacker L. 30 years of the mineralocorticoid receptor: Mineralocorticoid receptor antagonists: 60 years of research and development. J Endocrinol 2017; 234(1): T125-40.
[37]
Yang J, Young MJ. Mineralocorticoid receptor antagonists-pharmacodynamics and pharmacokinetic differences. Curr Opin Pharmacol 2016; 27: 78-85.
[38]
Kolkhof P, Jaisser F, Kim S-Y, Filippatos G, Nowack C, Pitt B. Steroidal and novel non-steroidal mineralocorticoid receptor antagonists in heart failure and cardiorenal diseases: Comparison at Bench and Bedside. Heart Fail 2016; 243: 271-305.
[39]
Ben Salem C, Badreddine A, Fathallah N, Slim R, Hmouda H. Drug-induced hyperkalemia. Drug Saf 2014; 37(9): 677-92.
[40]
Filippatos G, Anker SD, Böhm M, et al. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J 2016; 37(27): 2105-14.
[41]
Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: A randomized clinical trial. JAMA 2015; 314(9): 884-94.
[42]
Sato N, Ajioka M, Yamada T, et al. A randomized controlled study of finerenone vs. eplerenone in japanese patients with worsening chronic heart failure and diabetes and/or chronic kidney disease. Circ J 2016; 80(5): 1113-22.
[43]
Katayama S, Yamada D, Nakayama M, et al. A randomized controlled study of finerenone versus placebo in Japanese patients with type 2 diabetes mellitus and diabetic nephropathy. J Diabetes Complications 2017; 31(4): 758-65.
[44]
Lovic D, Stojanov V, Jakovljević B, et al. Prevalence of arterial hypertension in Serbia: PAHIS study. J Hypertens 2013; 31(11): 2151-7.
[45]
Lovic D, Erdine S, Catakoğlu AB. How to estimate left ventricular hypertrophy in hypertensive patients. Anadolu Kardiyol Derg 2014; 14(4): 389-95.
[46]
Faselis C, Boutari C, Doumas M, Imprialos K, Stavropoulos K, Kokkinos P. Novel drugs for hypertension and heart failure: Struggling for a place under the sun. Curr Pharm Des 2017; 23(10): 1540-50.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 24
ISSUE: 46
Year: 2018
Page: [5491 - 5499]
Pages: 9
DOI: 10.2174/1381612825666190215100502
Price: $58

Article Metrics

PDF: 41
HTML: 6
EPUB: 1
PRC: 1

Special-new-year-discount