Aldosterone and Mineralocorticoid Receptors in the Cardiovascular System

https://doi.org/10.1016/j.pcad.2009.12.003Get rights and content

Abstract

Aldosterone is currently thought to exert its physiologic effects by activating epithelial mineralocorticoid receptors, and its pathologic effects on the cardiovascular system via mineralocorticoid receptors in the heart and blood vessels. Recent studies have extended this understanding to include a reevaluation of the roles of aldosterone and mineralocorticoid receptor activation in blood pressure control; the rapid, nongenomic effects of aldosterone; the role of cortisol as a mineralocorticoid receptor agonist under conditions of redox change/tissue damage/reactive oxygen species generation; the growing consensus that primary aldosteronism accounts for approximately 10% of all essential hypertension; recent new insights into the cardioprotective role of spironolactone; and the development of third- and fourth-generation mineralocorticoid receptor antagonists for use in cardiovascular and other inflammatory disease. These findings on aldosterone action and mineralocorticoid receptor blockade are analyzed in the context of the prevention and treatment of cardiovascular disease.

Section snippets

Aldosterone and mineralocorticoid receptors: classic physiology

Aldosterone was first isolated in 1953 and characterized as the major mineralocorticoid hormone on the basis of its potent effects on unidirectional transepithelial sodium transport.1 It is commonly taught that the major stimulus to its secretion is angiotensin2, 3 and that the physiologic actions of aldosterone are homeostatic, preserving fluid and electrolyte status via a negative feedback loop - depletion of sodium or circulating volume leading to increased renin secretion, and the

Aldosterone and MR: classic pathophysiology

Primary aldosteronsism (Conn's syndrome) was first reported in 1954 by Dr Jerome Conn, who diagnosed aldosterone overproduction in a young woman with hypertension and hypokalemia, reversed by surgical removal of the affected adrenal.12 Although Conn believed that autonomous aldosterone secretion might cause up to 20% of essential hypertension, until recently it was thought and taught that it represented less than 1%, that it was a relatively benign form of hypertension, and that hypokalemia was

Aldosterone and MR: current physiology

The word ‘current’ is used in a loose sense, as many of the details have been published in the scientific literature for a decade or more, but are often yet to be included in textbooks or in current reviews. For aldosterone, the belief that angiotensin II is the primary driver of increased secretion needs to be refined. This assumption has been reinforced by the development and wide use of ACE inhibitors and angiotensin receptor blockers, and is not challenged at the clinical level despite

Aldosterone and MR: current pathophysiology

There are 2 major clinical situations where MR blockade is currently widely accepted as indicated - primary aldosteronism and heart failure. For primary aldosteronism, the current consensus is that autonomous aldosterone secretion inappropriate for sodium status is responsible for around 10% of essential hypertension.26 There is also consensus that adenoma represents only around one third of cases of primary aldosteronism, and bilateral hyperplasia the remainder; that hypokalemia is rare in

Heart failure: clinical notes

Whereas the RALES trial was in progressive (largely stage III) heart failure and EPHESUS was in heart failure post–myocardial infarction, MR antagonists should be considered as potentially beneficial across the heart failure spectrum. Low daily doses (12.5-25 mg spironolactone, 25-50 mg eplerenone) in combination with standard of care are recommended. Caution should be exercised in patients with impaired renal function, who may develop hyperkalemia even on the low doses recommended, despite

Hypertension: clinical notes

In patients with primary aldosteronism due to bilateral disease or unwilling/unable to undergo laparoscopic surgery for unilateral adenoma, MR antagonists are recommended. Spironolactone dosage is optimally modest (25-50 mg daily) to minimize antiandrogenic/progestational adverse effects, with higher doses used only if substantial BP elevation persists in the presence of additional antihypertensive medications. In a recent clinical study, eplerenone (50-100 mg daily) has been shown to be

Envoi

Consideration of clinical and experimental studies would appear to necessitate a radical reconsideration of the pathophysiologic role of aldosterone, the mechanism of MR activation in the context of tissue damage, and the way in which MR “antagonists” (more properly, partial agonists/partial antagonists) oppose the proinflammatory effects of MR activation. Such a radical reconsideration may be neither welcome nor popular: as noted 5 centuries ago:

“There is nothing more difficult and dangerous,

Statement of Conflict of Interest

The author declares that there are no conflicts of interest.

References (44)

  • FunderJ.W.

    The nongenomic actions of aldosterone

    Endocr Rev

    (2005)
  • KrozowskiZ.S. et al.

    Renal mineralocorticoid receptors and hippocampal corticosterone-binding species have identical intrinsic steroid specificity

    Proc Natl Acad Sci U S A

    (1983)
  • PearceP. et al.

    High affinity aldosterone binding sites (type 1 receptors) in rat heart

    Clin Exp Pharmacol Physiol

    (1987)
  • FunderJ.W. et al.

    Exclusion of corticosterone from epithelial mineralocorticoid receptors is insufficient for selectivity of aldosterone action: in vivo binding studies

    Endocrinol

    (1996)
  • FunderJ.W. et al.

    Mineralocorticoid action: target-tissue specificity is enzyme, not receptor, mediated

    Science

    (1988)
  • FunderJ.W. et al.

    Vascular type I aldosterone binding sites are physiological mineralocorticoid receptors

    Endocrinology

    (1989)
  • ConnJ.

    Primary aldosteronism: a new clinical syndrome

    J Lab Clin Med

    (1955)
  • PittB. et al.

    The effect of spironolactone on morbidity and mortality in patients with severe heart failure

    N Engl J Med

    (1999)
  • OkuboS. et al.

    Angiotensin-independent mechanism for aldosterone synthesis during chronic extracellular fluid volume depletion

    J Clin Invest

    (1997)
  • LevyD. et al.

    Distinguishing the antihypertensive and electrolyte effects of eplerenone

    J Clin Endocrinol Metab

    (2004)
  • Gomez-SanchezE.P.

    What is the role of the central nervous system in mineralocorticoid hypertension

    Am J Hyperten

    (1991)
  • Gomez-SanchezE.P. et al.

    ICV infusion of corticosterone antagonizes ICV-aldosterone hypertension

    Am J Physiol

    (1990)
  • Cited by (69)

    • Renin–angiotensin system blockade: Finerenone

      2017, Nephrologie et Therapeutique
      Citation Excerpt :

      Aldosterone binding to the ligand-binding domain of the mineralocorticoid receptors promotes a conformation change that allows the dissociation of the complex from chaperones which is associated with a rapid translocation to the nucleus where the mineralocorticoid receptor binds to hormone response elements and recruits specific coactivator proteins, allowing the transcription or repression of target genes [5–7]. However, aldosterone also exerts mineralocorticoid receptor-independent effects and in both mineralocorticoid receptor-dependent/independent effects, genomic and non-genomic effects have been described [4,6–10]. The relative contribution of mineralocorticoid receptor-dependent/independent and genomic/non-genomic effects of aldosterone to the pathogenesis of cardiovascular and renal diseases is uncertain [4,7,10].

    • Primary Aldosteronism: Challenges in Diagnosis and Management

      2015, Endocrinology and Metabolism Clinics of North America
    • What We Know about and What Is New in Primary Aldosteronism

      2024, International Journal of Molecular Sciences
    View all citing articles on Scopus
    View full text