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Prince Henry’s Institute of Medical Research, Clayton, Victoria, Australia 3168
Address all correspondence and requests for reprints to: John W. Funder, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton 3168, Victoria, Australia. E-mail: john.funder{at}princehenrys.org.
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MINIREVIEWS MAY HAVE several purposes, not all of which can be encompassed in an abbreviated format. Some (e.g. Ref. 1) attempt to cover the waterfront in terms of relevant publications, often useful as a guide to further reading; this is not such an offering. What this review aims to do is to set out the often overlooked context(s) in which rapid, nongenomic actions of aldosterone need to be considered, with particular emphasis where possible on distinguishing phenomenology from potentially physiological roles for such actions.
The area is one sometimes characterized by more data than analysis, and often by more heat than light. For the purposes of this review some things will be taken as givens, as follows: 1) that aldosterone has rapid, nongenomic effects; 2) that some, but perhaps not all, of these effects are mediated via activation of the classical intracellular mineralocorticoid receptor (MR); 3) that whereas such effects may sensitize or precondition the intracellular milieu for subsequent action of aldosterone via classical genomic pathways, they may also represent discrete physiological effects in their own right; and 4) that, perhaps most importantly, given the equivalent affinity of MR for aldosterone and the physiological glucocorticoids, demonstrating a rapid effect of subnanomolar aldosterone on a particular subcellular readout is evidence for MR activation, not for a physiological role for aldosterone. In vitro systems are immensely powerful for dissecting mechanisms, but ultimately they show what can happen, not what does happen.
One thing that does happen is that aldosterone secretion responds very rapidly to its two major physiological stimuli, angiotensin II and plasma [K+]. Of itself, this is not evidence for a necessarily equivalently rapid response role for aldosterone in homeostasis, but it allows for such roles. If we consider the time courses for the stimuli, dietary sodium deficiency via angiotensin elevation or potassium loading via elevated plasma [K+] are relatively protracted in onset and thus consistent with a relatively protracted homeostatic effector limb, that of Na+ retention/K+ excretion via the well-documented genomic effects of aldosterone on epithelial MR.
There are, however, in vivo situations in which rapid effects of aldosterone via nonepithelial MR are of particular homeostatic point. In terms of pathophysiology, the rapid rise of aldosterone in response to angiotensin II post hemorrhage is usually construed as important to conserve Na+ and water and thus to restore circulating volume; this is clearly the case. The finding, however, of 1) 11ß-hydroxysteroid dehydrogenase (11ß-HSD2) protected MR in the vascular wall (2), 2) rapid MR activation by cortisol in the presence of carbenoxolone to block 11ß-HSD2 and their blockade by the water-soluble MR antagonist RU28318 (3), and 3) the rapid decrease in forearm blood flow when picomolar levels of aldosterone are closely infused in vivo (4) equally clearly opens another possible role for aldosterone, that of a rapid, direct vasoconstrictor effect, in concert with catecholamines and angiotensin II, to maintain blood pressure and organ perfusion in the face of acute circulatory volume loss. Similar considerations would also seem to apply to acute catastrophic fluid and electrolyte loss in diarrheal disease.
The second area in which such direct vasoconstrictor actions of aldosterone presumably play a role is in the rapid accommodation of blood pressure to changes in posture. Such changes are recognized to constitute a potent, rapid stimulus to aldosterone secretion, and for decades clinicians have treated orthostatic hypotension by administration of fludrocortisone. Given the importance of 11ß-HSD2 in the selectivity of aldosterone activation of MR (5), nonepithelial sites in which the enzyme is expressed, such as vascular wall, appear prime candidates for physiological effects of aldosterone to modulate blood pressure and thereby blood flow. That extrarenal rather than renal MR activation is the predominant mechanism in terms of its role in blood pressure regulation is strongly suggested by a metaanalysis of the effects of eplerenone, a selective MR antagonist. In a dose-titration study in essential hypertensives, no correlation could be found at any dose between the hypotensive effect of MR blockade and the effect on plasma [K+] as an index of the epithelial effects of the drug (6).
The second caveat in interpreting studies showing aldosterone effects, rapid or via classical genomic mechanisms, is that of receptor specificity. One of the salient arguments initially advanced for the rapid effect of aldosterone being via a nonclassical, membrane-located receptor was that such effects were not mimicked by high concentrations of physiological glucocorticoids or blocked by spironolactone. Currently, there is ample evidence that classical MR mediate at least some of the rapid effects seen in vitro with aldosterone; it is logically not possible to exclude non-MR-mediated effects, and there is evidence from MR knockout (7) and expression (8) studies that rapid changes in Ca2+ flux may represent one such example. Attempts to isolate an aldosterone-specific membrane receptor have not proven fruitful to date; in other systems, steroids have been shown to modulate G protein-coupled receptors, which may ultimately prove the case for aldosterone.
In terms of MR-mediated effects, genomic or nongenomic, it is crucial to consider the context of MR occupancy and activation. In studies on patch-clamped rabbit cardiomyocytes (9), aldosterone has been shown to have a rapid (<15 min) effect to increase transmembrane ion flux, resulting in a 10-fold increase in pump current at physiological doses of aldosterone. This effect is inhibited by potassium canrenoate, but not actinomycin D, and blocked by specific antagonist protein kinase C
(PKC) peptides (and mimicked by PKC agonist peptides). In addition to being rapid (<15 min) in onset and nongenomic (not blocked by actinomycin D), the effect is long-lived, in that in cardiomyocytes isolated from rabbits pretreated in vivo with aldosterone, the elevated pump current can be rapidly (<15 min) reversed by PKC inhibition, despite the approximately 4-h time lapse preparing the cells for study.
It would thus be tempting to seek potential physiological roles for this well-characterized rapid nongenomic effect of aldosterone. Whereas it is likely that aldosterone has pathophysiological roles in the cardiomyocyte, nongenomic and/or genomic, there is evidence against a primary physiological role, on two counts. First, cardiomyocytes do not normally express 11ß-HSD2, so that, in common with other such tissues, MR are overwhelmingly occupied by physiological glucocorticoids. Experimentally, cardiomyocyte-selective overexpression of 11ß-HSD2, allowing aldosterone to access mouse cardiomyocyte MR in vivo, has been shown to be followed by cardiac hypertrophy and fibrosis (10), a response reminiscent of that seen in mineralocorticoid-treated rats given 0.9% NaCl solution to drink (11). The interpretation of these latter studies is that cardiomyocyte MR are normally overwhelmingly occupied by glucocorticoids, previously shown experimentally (12), in tonic inhibitory mode. In situations in which there is tissue damage, reactive oxygen species generation and change in intracellular redox status, such glucocorticoid-occupied MR may become activated, as suggested experimentally by inference (13, 14) or directly in preliminary studies on isolated cardiomyocytes (15). In the context of inappropriate salt status, or tissue damage, MR activation in cardiomyocytes has clearly deleterious effects. Whether or not there is a physiology, genomic or nongenomic, for (relatively) high aldosterone levels in low volume/salt deficiency situations via occupancy of a minority of cardiomyocyte MR remains to be determined.
A similar situation in which aldosterone has been shown to have major effects is on blood pressure via circumventricular MR (16, 17); whether this effect is genomic and/or nongenomic is moot, although its blockade by amiloride coadministered intracerebroventricularly (ICV) is evidence that nongenomic effects may be involved (18); blockade of the effect by coadministered RU28318 is similarly reasonably interpreted as evidence for a classical MR mediating the effect (19). The doses of aldosterone administered ICV are minute, far less than required to raise blood pressure administered systemically; the effect of aldosterone is progressively blocked by coadministered equal and 2-fold doses of corticosterone, reasonably interpreted as evidence for an action via MR unprotected by 11ß-HSD2 (17). The time course of blood pressure elevation is days/weeks, evidence not for a genomic vs. rapid nongenomic effect of MR activation, but of the multiple, complex, interacting physiological mechanisms to dampen blood pressure change. On such evidence, it is again tempting to ascribe and seek physiological roles for aldosterone in blood pressure control via circumventricular MR.
Such a possibility is in fact unlikely; pace the circumventricular area elaborating high concentrations of aldosterone locally, and there is no evidence for such a hot spot. The evidence against a role for circulating aldosterone levels having a physiological role on blood pressure via circumventricular MR is 2-fold. First, jr/s (salt-sensitive) rats respond to saline loading by rapidly elevating their blood pressure, an effect abrogated by ICV administration of RU28318 at the time of salt loading. This has reasonably been interpreted as evidence for an effect via MR, but the context is that of suppressed aldosterone levels in response to salt loading and unprotected (and thus overwhelmingly glucocorticoid-occupied) circumventricular MR (20). The second line of evidence comes from studies on the acute hypotensive effects of ICV injection of RU28318 in normotensive rats, which showed 20–30 mm Hg falls in blood pressure regardless of low, normal, or high salt intake, suggesting that circulating aldosterone levels are unrelated to blood pressure regulation via circumventricular MR (21).
If aldosterone does not play such a physiological role, genomic or nongenomic, the question remains of what does. As noted previously, such unprotected MR are normally overwhelmingly occupied by glucocorticoids, and we are only now becoming comfortable with the notion of an always-occupied receptor being activated (or not) by mechanisms other than ligand binding; other constitutively occupied receptors include hnf4 and ROR
, with perhaps the Drosophila receptor E75 the most extensively characterized in terms of mechanisms of activation (22). It is unlikely that the stimulus to activation of circumventricular glucocorticoid-occupied MR is reactive oxygen species generation, as in the failing cardiomyocyte. It is more likely that whether or not such MR are activated reflects neural input, with rapid responses to acute volume loss and postural change and sustained responses (genomic and/or nongenomic) to less obvious, and not necessarily electrolyte-related, changes. The caveat expressed earlier about in vitro studies would appear applicable at least to some extent to the in vivo situation; ICV administration of aldosterone is evidence for what the steroid can do, and not necessarily what it does.
The area of MR activation is one in which the usual direction of translational research, from benchtop to clinic, has in fact been reversed. The RALES (23), EPHESUS (24), and 4E trials (25) showed conclusively that MR blockade, on top of standard of care, was of major therapeutic benefit. This was initially, and unfortunately often still commonly, trumpeted as evidence for aldosterone blockade; the uncomfortable fact that in all three clinical trials, baseline levels of aldosterone were low normal, and sodium status unremarkable, was conveniently overlooked. Similarly, the way in which an always-occupied MR, in the hippocampus or the cardiomyocyte, can function as a signal transducer is commonly assigned to the too-hard basket. Since RALES, EPHESUS, and 4E, however, a realization is emerging that MR have roles, cardiovascular and presumably other, in addition to and quite distinct from their roles in electrolyte homeostasis in response to aldosterone. This is not surprising, given that MR evolved well before the emergence of aldosterone in terrestrial vertebrates, as a high-affinity corticoid receptor (26).
In this context, debating rapid nongenomic vs. genomic would appear to be an increasingly futile exercise (see Table 1
). The classical epithelial effects of aldosterone on MR to retain Na+ and excrete K+ are clearly genomic (although not necessarily uniquely so). The acute effects of aldosterone on the vasculature are clearly nongenomic, which in no way precludes additional genomic effects. For some effects of MR activation (e.g. central effects on blood pressure and cardiac fibrosis), the time courses and the complexity of the responses are such that distinguishing nongenomic and genomic is not possible. And finally, aldosterone action and MR activation are overlapping but not coterminous domains; any consideration of acute aldosterone actions in the cardiovascular system neglects this distinction at its own peril.
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First Published Online August 31, 2006
Abbreviations: 11ß-HSD2, 11ß-Hydroxysteroid dehydrogenase; ICV, intracerebroventricular; MR, mineralocorticoid receptor; PKC, protein kinase C.
Received June 19, 2006.
Accepted for publication July 13, 2006.
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