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Prince Henry’s Institute for Medical Research Clayton, Victoria 3168, Australia
Address all correspondence and requests for reprints to: Professor John W. Funder, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton, Victoria 3168, Australia. E-mail: john.funder{at}phimr.monash.edu.au.
For almost a decade, there have been reports of the extraadrenal synthesis of aldosterone, in vascular wall (1, 2, 3, 4, 5, 6), heart (7, 8, 9, 10, 11, 12, 13, 14), and brain (15). What might initially have seemed a biologic curiosity, the tissue renin-angiotensin system come full circle, assumed a potential pathophysiologic role with the publication of the RALES (Randomized Aldactone Evaluation Study) trial (16). In RALES, the addition of low-dose spironolactone to standard of care in progressive heart failure produced an improvement of 30% in survival, and of 35% in hospitalization, enough to interest even the health economists. But the patients had normal plasma levels of aldosterone and unremarkable sodium status: what, then, was the spironolactone antagonizing? The temptation to invoke cardiac synthesis of aldosterone, and its paracrine action at the local level, proved irresistible. Investigators around the world—the writer included (14)—devoted time and resources to seeking PCR and/or immunoassay evidence.
The paper by Elise Gomez-Sanchez et al. (17) in the current issue of Endocrinology, taken with the recent presentation by Eleanor Davies at the International Aldosterone Conference (18), represents a line in the sand: the heart cannot make aldosterone. In the cool light of day it was always improbable, even before the current immunoassay and PCR studies. Gomez-Sanchez et al. (17) compare aldosterone synthase (CYP11B2) levels in adrenal gland and heart of rats on high-salt, normal, and low-salt diets. Ventricular levels of CYP11B2 mRNA were one millionth those in the adrenal gland: remember that this is whole adrenal, with CYP11B2 expressed uniquely in the few percent of cells that constitute the zona glomerulosa. Under low-salt conditions, ventricular CYP11B2/GAPDH levels increased approximately 20-fold, in parallel with plasma aldosterone levels.
In the adrenal glomerulosa a number of enzymes—side chain cleavage, 3ßhydroxysteroid dehydrogenase, 21-hydroxylase—convert cholesterol to deoxycorticosterone, the major substrate for aldosterone synthase. In various studies (e.g. Refs.13, 14), PCR levels of these enzymes have been measured as less than 1–0.01% those in the adrenal. Even disregarding the spatial details of adrenal mitochondrial substrate presentation, at such levels all the enzymatic steps become rate limiting. If we take an average value of 0.1% for the enzymes producing deoxycortisone, and the Gomez-Sanchez value of one millionth for aldosterone synthase, we arrive at a figure of 10–15.
The heart is certainly bigger than the adrenals, but 10–15 is a substantial offsetting factor when cardiac synthetic rates of aldosterone synthase equivalent to those in the adrenal have been claimed (7, 8, 9, 12, 19), or approximately 20% elevations in coronary sinus aldosterone levels over those in aortic blood (20). And even if cardiac aldosterone synthesis were confined to one cell in a thousand—and the enzymes expressed only in those cells—the level of aldosterone synthase would still be one thousandth that in whole adrenal, of which the glomerulosa is only a few percent of cells. Still not very impressive, and there goes the paracrine hypothesis.
The suspension of disbelief became even more difficult in some of the earlier reports, for example that the heart contained 14 times more aldosterone per unit mass than the plasma (9). This is not consistent with the findings of the Gomez-Sanchez study, where regardless of salt intake plasma and cardiac levels correlated closely, on the expected 1:1 basis. Cardiac aldosterone levels were, again as expected, half those on normal salt intake, again in contrast with a previous claim that cardiac aldosterone synthesis was stimulated not only by angiotensin II, but (counterintuitively) by high salt intake (8).
Perhaps the most telling in vivo evidence against a discernible pathophysiologic role for cardiac aldosterone synthesis comes from the studies by Ricardo Rocha and colleagues on the vascular and perivascular effects of angiotensin II infusion to rats with 0.9% NaCl to drink (21). In this model, the induced hypertension is adrenal independent, and unaffected by adrenalectomy (or administration of the selective mineralocorticoid receptor eplerenone). The coronary and perivascular inflammatory response (Fig. 1A
), however, is completely abrogated by adrenalectomy (Fig. 1B) and restored by aldosterone infusion (Fig. 1C). If cardiac synthesis of aldosterone were driven by angiotensin and high salt, Fig. 1B might be expected to look not all that different from Fig. 1A: res ipsa loquitur.
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Why put so much store on the present paper (17), given the mass of prior sightings? One reason is that the Gomez-Sanchez laboratory has produced the most specific antialdosterone antisera, and the most sensitive RIAs, that are available today. They—and Eleanor Davies et al. similarly (18)—have performed careful PCR assays, appropriately controlled and with scrupulous attention to excluding contaminants. Finally, the Gomez-Sanchez study found no difference in cardiac aldosterone levels between adrenalectomized rats, and adrenalectomized rats injected 3 h earlier with deoxycorticosterone: in the former group plasma deoxycortisone levels were undetectable, and in the latter group greater than 100 nM.
And yet... even though plasma aldosterone levels were measurable in only one adrenalectomized rat, 30% of adrenalectomized rats (25 of 84, adrenalectomized 2–8 d) had measurable cardiac levels. Levels were low (
30 pM), less than 20% those in high-salt rats, and with measurable levels less frequent in 7- to 8-d adrenalectomized animals. In their discussion, Gomez-Sanchez et al. (17) hedge their bets—"The finding that aldosterone in the heart was detectable in approximately 30% of hearts from adrenalectomized animals suggests that the heart is capable of synthesizing a very small amount of aldosterone. However the finding that corticosterone, present in approximately 400 times the concentration of aldosterone in the intact heart, becomes undetectable in the hearts of adrenalectomized rats suggests that no significant synthesis of corticosteroids occurs in the heart."
An alternative explanation for the residual immunoreactive aldosterone in cardiac muscle extracts from adrenalectomized rats may be that it is tethered, or bound, perhaps via an interaction through the very reactive signature aldehyde group at carbon 18. Normally greater than 99% of aldosterone exists in the 11,18 hemiacetal form, interpreted as protecting it from enzymatic attack by 11ß-hydroxysteroid dehydrogenase in epithelial mineralocorticoid target tissues (24, 25). Perhaps conditions in the heart are such that the very low circulating levels of 18-aldehyde form are bound in the tissue and released by the extraction procedure. Bound in this way, of course, they are not part of the free levels of aldosterone that determine mineralocorticoid receptor occupancy and activation.
There were powerful drivers to support the proposition that the heart makes aldosterone. The boundaries between classical endocrine and other tissues have dissolved, at least for peptide hormones, in the case of the heart by the demonstration of its ability to secrete natriuretic peptides. Secondly, it appeared to make sense of the spironolactone effect in RALES, although more recently an alternate explanation for the beneficial effects of mineralocorticoid receptor blockade in heart failure has been suggested (26). Finally, it had the fatal attraction of novelty, of pushing the envelope, challenging the accepted wisdom. Like the fantasy of molecules leaving their imprint on water at dilutions exceeding Avogadro’s number (27), it raised serious number issues, disregarded at our peril. It may now be time to put it behind us, and to get on with the business of cardiovascular endocrinology.
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Received August 12, 2004.
Accepted for publication August 16, 2004.
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