Published online before print September 19, 2005, doi: 10.1161/01.HYP.0000184227.75221.6e
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(Hypertension. 2005;46:643.)
© 2005 American Heart Association, Inc.
Editorial Commentaries |
Relative Aldosterone Excess
Relative to What?
From Prince Henry’s Institute of Medical Research, Clayton, Victoria, Australia.
Correspondence to Professor John W. Funder, Prince Henry’s Institute of Medical Research, Monash Medical Centre, 247 Clayton Rd, PO Box 5152, Clayton, Victoria, Australia 3168. E-mail john.funder{at}phimr.monash.edu.au
There is clear evidence that the vessel wall is an aldosterone target tissue, and that aldosterone at physiological levels produces vasoconstriction by genomic and rapid nongenomic actions.1 Similarly, in clinical studies cited by Duffy et al,2 patients with primary aldosteronism show impaired flow-mediated dilatation among other indices of endothelial dysfunction;3,4 in addition, mineralocorticoid receptor blockade reverses endothelial dysfunction in patients with hypertension or heart failure.4,5 In this issue of the journal Duffy et al2 explore vasodilator responses to methacholine, nitroprusside, and verapamil over a wide dose range in good-sized cohorts of hypertensive and normotensive subjects, to establish possible correlations with renin-angiotensin-aldosterone status. This is clearly a worthwhile undertaking, although the authors candidly admit they had expected to find elevated renin in hypertensives to be correlated with most marked impairment in vasodilatation and, in fact, found the opposite.
That said, there are several issues of interpretation and analysis that need to be raised. First is the usage "relative aldosterone excess" in the title and throughout the article. No differences between hypertensives and normotensives were seen in plasma aldosterone levels nor in either group divided into quartiles, with the exception of the highest renin quartile among normotensives: the significantly higher aldosterone levels in this subgroup may reflect nothing more sinister than lower sodium intake, which was unfortunately neither measured nor controlled. "Relative aldosterone excess" is thus relative to measured plasma renin levels, which makes the common but dangerous assumption that the major determinant of aldosterone secretion is the renin-angiotensin system. The most telling refutation of this assumption is the angiotensinogen-/- mouse, which responds to a low-sodium diet by an elevation of plasma aldosterone levels indistinguishable from wild type, and only shows a lesser response when the diet is low in potassium as well.6
In the absence of any index of sodium or potassium status in the hypertensive subjects, or even of plasma electrolyte levels, it is impossible to say whether or not the aldosterone levels are normal or elevated for the sodium status of the patients. There are many studies showing aldosterone levels per se not to be vasculotoxic, but only in the context of inappropriate sodium status. Experimentally, very high doses of aldosterone, far above physiological, do not cause cardiovascular damage to rats maintained on a low-salt diet. Similarly, high plasma aldosterone levels are a normal, protective, homeostatic response to sodium restriction in human subjects. The only way that "relative aldosterone excess" has any purchase is in the context of sodium status; just how inappropriate salt for aldosterone status plays its deleterious part is currently unknown.
The second major reservation that needs to be applied to the findings is the implications of the major discrepancy between the bottom panels of Figures 1 and 42 This discrepancy is among the findings that are baldly presented but not further discussed. The authors show a very muted vasodilator response to nitroprusside in the lowest renin quartile but a very brisk response to the same stimulus in the highest aldosterone to renin quartile. Put simply, the most likely explanation of this remarkable difference is that of a mistake. It may be that the group of 10 low renins (values 0.1 to 0.3 ng/mL per hour) is not exactly the same as the highest quartile in terms of aldosterone to renin ratio; a glance at Table 12 shows that it would be surprising if there were not 8 or 9 patients common to both groups. Despite the high variances, the mean values for the ratio in quartile 1 is 3-fold that in quartile 2, 7-fold that in quartile 3, and 12-fold that in quartile 4 (mirroring the plasma renin values), not unexpectedly given the flat, normal aldosterone levels.
The probability that the 2 groups (lowest plasma renin quartile, highest aldosterone-renin ratio quartile) very largely overlap is underscored by the near identical profiles shown in the top panels of Figures 1 and 4.2 Even if, as the authors note, "not all participants had all agonists" the populations shown in Figures 1 and 4 are identical, merely segregated into quartiles by different (but highly related) indices. If Figures 1 and 4, on revisiting, are both correct, then the authors have a fascinating and possibly very illuminating finding on their hands. Before a dehiscence between stimulating NO production (methacholine) and acting as an NO donor (nitroprusside) is attributed to aldosterone/renin ratio, net of plasma renin per se, it would be useful to know the overlap between the 2 quartiles, and the vasodilator responses when patients are segregated into quartiles on the basis of aldosterone levels.
It would also be useful to see some analysis of the clear differences between normotensive and hypertensive subjects, which similarly may shed light on what is a complex and sometimes conflicted area. Much of the complexity stems from the lack of distinction between physiological stimuli of the renin-angiotensin-aldosterone system (eg, sodium deficiency) and exogenous, nonphysiological inputs (eg, angiotensin infusion), in which the normal homeostatic negative feedback mechanisms cannot operate. Much of the conflict is also in a sense artifactual and might be, in part at least, resolved by acknowledging that most mineralocorticoid receptors are occupied by normal circulating levels of glucocorticoids.7 Under normal conditions, physiological glucocorticoids act as mineralocorticoid receptor antagonists,8 but when the protective enzyme 11ß-hydroxysteroid dehydrogenase is blocked or deficient (in epithelia, or the vessel wall), cortisol becomes a mineralocorticoid receptor agonist9; the same antagonist-to-agonist change is seen when intracellular redox state is altered by generation of reactive oxygen species.10 The focus on aldosterone, rather than mineralocorticoid receptor status, is thus less likely to yield unequivocal results than studies using receptor antagonists, which block the effect of whatever agonist. If, on the other hand, the data in Figures 1 and 42 can be validated, the present article may make a much more important contribution than the authors, who set out to prove the opposite, ever dreamed of.
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Footnotes |
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The views in this editorial commentary are not necessarily those of the editors or of the American Heart Association.
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References |
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 Top References |
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1. Funder JW. The nongenomic actions of aldosterone. Endocr Rev. 2005; 26: 313–321.
2. Duffy SJ, Biegelsen ES, Eberhardt RT, Kahn DF, Kingwell BA, Vita JA. Low renin hypertension with relative aldosterone excess is associated with impaired nitric oxide-mediated vasodilation. Hypertension. 2005; 46: 707–713.
3. Taddei S, Virdis A, Mattei P, Salvetti A. Vasodilation to acetylcholine in primary and secondary forms of human hypertension. Hypertension. 1993; 21: 929–933.
4. Nishizaka MK, Zaman MA, Green SA, Renfroe KY, Calhoun DA. Impaired endothelium-dependent flow-mediated vasodilation in hypertensive subjects with hyperaldosteronism. Circulation. 2004; 109: 2857–2861.
5. Farquharson CA, Struthers AD. Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation. 2000; 101: 594–597.
6. Okubo S, Niimura F, Nishimura H, Takemoto F, Fogo A, Matsusaka T, Ichikawa I. Angiotensin-independent mechanism for aldosterone synthesis during chronic extracellular fluid volume depletion. J Clin Invest. 1997; 99: 855–860.[Medline] [Order article via Infotrieve]
7. Funder JW, Myles K. Exclusion of corticosterone from epithelial mineralocorticoid receptors is insufficient for selectivity of aldosterone action: in vivo binding studies. Endocrinology. 1997; 137: 5264–5268.
8. Alzamora R, Michea L, Marusic ET. Role of 11beta-hydroxysteroid dehydrogenase on nongenomic aldosterone effects in human arteries. Hypertension. 2000; 35: 1099–1104.
9. Qin W, Rudolph AE, Bond BR, Rocha R, Blomme EA, Goellner JJ, Funder JW, McMahon EG. A Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure. Circ Res. 2003; 93: 69–76.
10. Funder JW. Is aldosterone bad for the heart? Trends Endocrinol Metab. 2004; 15: 139–142.[CrossRef][Medline] [Order article via Infotrieve]
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