| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Cardiology Royal North Shore Hospital and University of Sydney Sydney 2065, Australia
Address all correspondence and requests for reprints to: A. S. Mihailidou, Department of Cardiology, Royal North Shore Hospital and University of Sydney, Sydney 2065, Australia. E-mail: amihaili{at}doh.health.nsw.gov.au.
Until recently, aldosterone effects have been distinguished as acute nongenomic vs. more persistent genomic actions. Nongenomic actions are characterized by rapid onset and cannot be blocked by spironolactone nor mimicked by cortisol. On this basis, these rapid nongenomic effects of aldosterone were attributed to a membrane receptor, distinct from the classical mineralocorticoid receptor (MR), although such a receptor has not been characterized to date. Recently, however, Mano et al. (1) reported specific binding in plasma membranes of cardiac myocytes, with maximal levels of only 10.3 ± 0.4 fmol/mg protein, and no correlation with functional data.
The paper by Michea et al. (2) in the current issue of Endocrinology provides strong additional evidence that both the nongenomic and genomic actions of aldosterone, at least in cardiovascular tissues, are mediated via the same, classical MR. The new mineralocorticoid antagonist, eplerenone, which binds specifically to the cytosolic receptor (3, 4, 5, 6), blocks the rapid aldosterone effect on intracellular Ca2+ and pH as well as aldosterone-induced vasoconstriction. From other recent studies, there is a growing body of evidence that rapid nongenomic effects of aldosterone on vascular smooth muscle cells (7, 8) and cardiomyocytes (9, 10) are similarly mediated via classical MRs.
A previous study from the Marusic laboratory (7) showed that human vascular smooth muscle cells express 11ß-HSD1 and 11ß-HSD2, and nanomolar concentrations of aldosterone acutely (<5 min) increased intracellular pH in these cells. This effect was mediated by acute activation of the Na+/H+ exchanger, as it was blocked by the amiloride derivative ethylisoprolpylamiloride but not spironolactone; in contrast, the water soluble, open E-ring MR antagonist RU28318 blocked the aldosterone-induced increase in pH. In keeping with other studies on the rapid effects of aldosterone, cortisol alone was without effect. When, however, the cortisol-metabolizing, reduced nicotinamide adenine dinucleotide-generating enzyme 11ß-HSD2 is blocked by addition of carbenoxolone, the glucocorticoid becomes active, mimicking the aldosterone action on intracellular pH.
These actions of aldosterone are likely to be mediated by the classical MR, in that the Na+/H+ exchanger is plasma membrane located, whereas 11ß-HSD2 is largely in the endoplasmic reticulum, and therefore a plasma membrane located receptor is unlikely to be protected by 11ß-HSD2. In addition to these in vitro studies, rapid, nongenomic actions of aldosterone have recently been reported in vivo (11). Patients received a brief infusion of a modest level of aldosterone into one brachial artery and forearm blood flow and vascular resistance was measured. Compared with the contralateral forearm, a significant decrease in flow was observed at 4 min after the start of infusion, reaching a nadir at 12 min and returning to baseline over a similar period.
Rapid, nongenomic aldosterone effects via classical MRs have also been shown in rabbit cardiac myocytes (10), where aldosterone increases Na+/K+/2Cl– cotransport and decreases Na+/K+ pump activity. The acute effect of aldosterone on cotransporter activity is not blocked by spironolactone or canrenone. In contrast, the open E-ring, water-soluble MR antagonist potassium canrenoate blocks the aldosterone effect, just as RU28318 did in vascular smooth muscle cells. This effect of aldosterone is mediated via protein kinase C (PKC)
at both cotransporter and pump level. Aldosterone-induced increase in cotransporter activity was blocked by staurosporine, bisindolylamide, and PKC-specific inhibitory peptide; in addition, PKC agonist peptide mimicked the aldosterone action, whereas PKC
, PKC
, and scrambled PKC agonist peptides did not.
In rabbits chronically infused with aldosterone, the lowered pump activity in cardiac myocytes was acutely (
15 min) restored by PKC inhibition. These studies show that rapid effects of aldosterone on Na+-K+ pump activity are nongenomic and are specifically PKC mediated; in addition, they show that such nongenomic effects can be prolonged (7 d) and long-lived (
4-h isolated cardiomyocyte preparation time) and can persist in the absence of aldosterone over the time of cell preparation. These rapid, maintained, and persistent effects can in turn be rapidly reversed by PKC antagonist administration. These effects of aldosterone have been shown to be blocked by the classical MR antagonist spironolactone in vivo (9), further evidence for an aldosterone effect via the classical MR and providing additional evidence for maintained or chronic nongenomic effects. The simple distinction between aldosterone effects being acute nongenomic vs. more persistent genomic actions may thus need to be radically reconsidered on the basis of these recent studies, considered in toto. None of them exclude the possibility of non-MR-mediated rapid nongenomic effects; what they do constitute, however, is a growing body of evidence that in the cardiovascular system, at least, a variety of nongenomic effects are clearly mediated by classical intracellular mineralocorticoid receptors.
 |
Footnotes |
|---|
Received December 7, 2004.
Accepted for publication December 15, 2004.
|
References |
|---|
 Top References |
|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
