Published online before print February 27, 2006, doi: 10.1161/01.HYP.0000203732.03784.3b
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(Hypertension. 2006;47:634.)
© 2006 American Heart Association, Inc.
Editorial Commentaries |
Mineralocorticoid Receptors and Cardiovascular Damage
It’s Not Just Aldosterone
From Prince Henry’s Institute of Medical Research, Clayton, Victoria, Australia.
Correspondence to John Funder, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton, Victoria, Australia 3168. E-mail john.funder{at}princehenrys.org
A decade before aldosterone was isolated and characterized, Hans Selye showed that administration of deoxycorticosterone acetate to rats sensitized by salt loading produced a vascular inflammatory response (polyarteritis) and tissue fibrosis. Fifty years later, Karl Weber and his colleagues showed that aldosterone and inappropriate salt intake produced cardiac hypertrophy and fibrosis1; this response is bilateral, independent of blood pressure,2 and preceded by progressive perivascular and interstitial inflammation.3 Clinically, patients with primary aldosteronism are more at risk than essential hypertensive patients with comparable blood pressure elevation, similarly suggesting a pathophysiological role for aldosterone in the cardiovascular system. On the basis of this evidence, experimental and clinical, there is thus no doubt that blocking aldosterone action in such circumstances is beneficial in terms of progression and outcomes.
It is, however, not as simple as that. In the present issue of Hypertension, Nagata et al4 show that mineralocorticoid receptor blockade attenuates cardiac hypertrophy and failure in low-renin, low-aldosterone hypertensive rats. The model is straightforward: salt sensitive Dahl rats are started at 7 weeks on an uncompromisingly high (8%) salt intake to which they not surprisingly respond by marked cardiac hypertrophy and clear signs of cardiac failure at age 19 weeks. Animals given eplerenone (30 or 100 mg/kg bw in the chow) to block mineralocorticoid receptors are progressively protected in terms of a number of cardiac/pulmonary indices. The authors conclude that in this model, mineralocorticoid receptor activation is not by the low levels of aldosterone, but by corticosterone, which circulates at total concentrations 
2000x those of aldosterone and has at least equal affinity for mineralocorticoid receptors.5,6
The clinical observations supporting a role for glucocorticoid/activation of mineralocorticoid receptors are very persuasive. For decades it has been known that congenital deficiency of the enzyme 11ß hydroxysteroid dehydrogenase (or its blockade in licorice abuse) is followed by marked sodium retention, reflecting activation of renal tubular mineralocorticoid receptors by normal cortisol levels. Two things are often forgotten about this enzyme-regulated receptor activation system normally allowing aldosterone selectivity in mineralocorticoid target tissues. The first is that the enzyme debulks intracellular glucocorticoids rather than completely metabolizing them to receptor-inactive products: the upshot is that even when the enzyme is operating at full capacity intracellular glucocorticoid levels are 10x those of aldosterone, and most mineralocorticoid receptors are occupied but not activated by glucocorticoids.7 The second thing often forgotten is that NAD is a cosubstrate for 11ß hydroxysteroid dehydrogenase, and that changes in intracellular redox state, reflecting changes in NAD/NADH ratios, are a consequence of the operation (or blockade) of the enzyme.
Enter the clinical trials of spironolactone and eplerenone over the past decade. In progressive (New York Heart Associate Class III) heart failure, low dose (26 mg/d average) spironolactone added to standard of care produced a 30% improvement in survival, and 35% less hospitalization, than standard of care alone.8 In post-myocardial infarct heart failure the selective mineralocorticoid receptor antagonist eplerenone similarly showed additive effects to standard therapy.9 In essential hypertensives, eplerenone showed comparable cardiac effects and better renal protection than enalapril, with combined therapy even more effective.10 One salient but often conveniently overlooked feature of all 3 trials was that pretreatment plasma aldosterone levels were in the low normal range and sodium status unremarkable. The present article by Nagata et al4 is thus the sound of the other shoe dropping.
In a complex area such as pathophysiology no study can be absolutely watertight, and the present study is no exception. Crucial to the development of coronary vascular inflammation and cardiac fibrosis is an inappropriate aldosterone/salt balance: rats on a low salt diet do not show the pathological changes seen in those infused with the same dose of aldosterone but drinking 0.9% NaCl solution. The Dahl salt sensitive rats on 8% NaCl solution show plasma aldosterone levels half those of controls maintained on 0.3% NaCl chow and water: it takes no giant leap of imagination to think that aldosterone levels half those in controls may be inappropriately high in the context of an obligate 8% salt intake. How mineralocorticoid receptor activation in a low salt context is clearly not cardiovasculotoxic, whereas the same degree of activation with high salt is, remains enigmatic.
That said, the evidence adduced is very persuasive. The authors have made multiple determinations of cardiac structure and function that change in response to the high salt intake, and all of which are progressively improved by eplerenone. Body weight and blood pressure do not vary significantly between groups; the most sensitive markers of mineralocorticoid receptor blockade are mRNA levels for atrial natriuretic peptide, 11ß hydroxysteroid dehydrogenase Type I, and monocyte chemoattractant protein; in no case, however, does eplerenone restore levels absolutely to control.
What is important here is that cardiac myocytes do not express 11ß hydroxysteroid dehydrogenase Type II and are thus not candidate physiological aldosterone target tissues. Given the 1:4000 aldosterone to corticosterone ratio of measured plasma levels in the Dahl rats on an 8% sodium intake, it is difficult to envisage how aldosterone can ever occupy cardiomyocyte MR, thus prompting the search for alternate activating ligands. There is increasing evidence that nuclear receptors as a class can be activated by agents other than their cognate ligand, and there are early reports, for instance, of mineralocorticoid receptor activation by angiotensin. This is unlikely in the present context of suppressed renin, although the authors did note increased cardiac expression of angiotensin-converting enzyme and angiotensin type 1 receptor genes. Occam’s razor, if nothing else, points to the activation of mineralocorticoid receptors in cardiomyocytes by corticosterone, converted from tonic inhibitor to receptor agonist by the changed cellular context.
And the changed cellular context in the cardiomyocyte in heart failure and the vascular wall in hypertension is that of the generation of reactive oxygen species and the consequent change in intracellular redox state. The present article documents the changes in GSH/GSSG ratio with high salt and its progressive normalization by eplerenone. Changes in intracellular reactive oxygen species are widely recognized as a consequence of inappropriate mineralocorticoid receptor activation; the present article, taken with previous indirect evidence,11 strongly suggests that in addition to being a consequence, the redox changes are also a driver, leading to a vicious cycle of spiraling tissue damage. Interrupting this vicious cycle by mineralocorticoid receptor blockade, by an obligate antagonist such as spironolactone or eplerenone, thus can be anticipated to very effectively normalize the structural and functional sequelae. This is what Nagata et al have done in their article, and in its sweep and completeness lies its strength.
As endocrinologists we almost unconsciously assign primacy to hormones, sometimes to the detriment of a broader consideration of the receptor(s) involved in hormone action. This has been the case par excellence for aldosterone and mineralocorticoid receptors and has led our essentially ignoring potential (patho)physiological roles for mineralocorticoid receptors in nonepithelial tissues unprotected by 11ß hydroxysteroid dehydrogenase Type II. Mineralocorticoid receptors are present in fish and evolved well before aldosterone synthase (CYP11B2); the evolutionary driver in their distinction from the other members of the subfamily (androgen/progesterone/glucocorticoid receptors) has been cortisol, not aldosterone.12 The highest concentration of mineralocorticoid receptors is in the hippocampus, always occupied by glucocorticoids, with presumably a range of functions awaiting exploration. Activation of glucocorticoid-occupied mineralocorticoid receptors in the heart by redox change, as suggested by Nagata et al,4 may be one of a number of mechanisms whereby a bivalent ligand such as cortisol/corticosterone can switch from tonic inhibitory to agonist mode. The therapeutic implications are clear, but the subcellular mechanisms involved are still as through a glass, darkly. It should be enormous fun to find out.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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1. Brilla CG, Weber KT. Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med. 1992; 120: 893–901.[Medline] [Order article via Infotrieve]
2. Young M, Head G, Funder J. Determinants of cardiac fibrosis in experimental hypermineralocorticoid states. Am J Physiol. 1995; 269: E657–E662.[Medline] [Order article via Infotrieve]
3. Rocha R, Martin-Berger C, Yang P, Scherrar R, Delyani J, McMahon E. Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart. Endocrinology. 2002; 143: 4828–4836.
4. Nagata K, Obata K, Xu J, Ichihara S, Noda A, Kimata H, Kato T, Izawa H, Murohara T, Yokota M. Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and failure in low-aldosterone hypertensive rats. Hypertension. 2006; 47: 656–664.
5. Funder JW. Is aldosterone bad for the heart? Trends Endocrinol Metab. 2004; 15: 139–142.[CrossRef][Medline] [Order article via Infotrieve]
6. Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE, Evans RM. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science. 1987; 237: 268–275.
7. Funder JW, Myles K. Exclusion of corticosterone from epithelial mineralocorticoid receptors is insufficient for selectivity of aldosterone action: in vivo binding studies. Endocrinology. 1996; 137: 5264–5268.[Abstract]
8. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999; 341: 709–717.
9. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309–1321.
10. 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.
11. Ward MR, Kanellakis P, Ramsey D, Funder JW, Bobik A. Eplerenone suppresses constrictive remodeling and collagen accumulation after angioplasty in porcine coronary arteries. Circulation. 2001; 104: 467–472.
12. Hu X, Funder JW. The evolution of mineralocorticoid receptors. Mol Endocrinol. 2005;Sept 29:Epub.
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