Aldosterone and Mineralocorticoid Receptors in the Cardiovascular System
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.
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2017, Nephrologie et TherapeutiqueCitation 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
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