Tae-Yon Chun and J.

Howard Pratt
Nongenomic Renal Effects of Aldosterone: Dependency on NO and Genomic Actions
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Copyright 2006 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Hypertension
doi: 10.1161/01.HYP.0000205225.88721.2c
2006;47:636-637; originally published online March 6, 2006; Hypertension.
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Nongenomic Renal Effects of Aldosterone
Dependency on NO and Genomic Actions
Tae-Yon Chun, J. Howard Pratt
T
here is increasing evidence for a dependency on
aldosterone in the development of hypertension.
1
How
aldosterone influences the physiology that determines
blood pressure or for that matter promotes the pathophysiol-
ogy of high blood pressure turns out to be less than straight-
forward. There is the genomic pathway that begins with the
binding of aldosterone to the classical mineralocorticoid
receptor (MR) and ends with sodium reabsorption at the distal
nephron. But aldosterone can convey nongenomic influences
as well, actions that have received less attention, possibly in
part because they seem counterintuitive to our genomic view of
biology. Adding to the complexity of aldosterones actions is
the fact that there are also nonepithelial (nondistal nephron)
targets of aldosterone, such as the heart, the vasculature, the
kidney, and other sites. In this issue of Hypertension, Schmidt
et al
2
describe a rapid (thus nongenomic) effect of adminis-
tered aldosterone to increase resistance in renal vasculature (a
nonepithelial target) in healthy human subjects. The findings
follow on the heels of a rather large body of work on the
genomic actions of aldosterone.
Aldosterones nongenomic effects were first recognized
more than a decade before an aldosterone-inducible gene was
identified in the late 1990s.
3
A nongenomic action character-
istically occurs almost immediately, usually within several
minutes,
4
before sufficient time has elapsed for gene tran-
scription and synthesis of new protein (the time it takes
aldosterone to increase the sodium current, a genomic effect,
is 30 minutes). A novel aldosterone receptor for non-
genomic signaling has yet to be identified, but it would seem,
if indeed a specific receptor exists, that most likely it is
membrane associated. A role for the classical MR has not
been ruled out
5
although the MR antagonist, spironolactone,
is not usually inhibitory nor is the response lost in MR
knockout mice. Nongenomic responses elicited by aldoste-
rone are accompanied by activation of early signal transduc-
tion pathways with increases in intracellular calcium, inositol
triphosphate, diacylglycerol, and cAMP together with activa-
tion of protein kinase C. Most previous nongenomic studies
of aldosterone were carried out in vitro or ex vivo, thus
limiting the chance for observing potential interactions with
other systems. Nongenomic and genomic actions of aldoste-
rone might, for example, importantly interact as was sug-
gested by the in vivo study of Schmidt et al.
They found that the effect of aldosterone on renal vasculature
occurred only when endothelial NO synthase (eNOS) was inhib-
ited by simultaneously treating with N
G
monomethyl-L-arginine
(L-NMMA); inhibition of eNOS appeared to unmask a non-
genomic effect of aldosterone. Although one could argue that
this necessary manipulation made conditions too pharmaco-
logical, it can just as easily be viewed as a replication of the
endothelial dysfunction that is associated with increased risk
for cardiovascular disease, as might occur, for example, in
patients with the metabolic syndrome. Indeed, the requisite
for eNOS inhibition suggests that certain nongenomic vascu-
lar effects of aldosterone become manifest only when there is
a loss of endothelial integrity. This was nicely demonstrated
in earlier studies carried out by Arima et al
6
using isolated
renal arterioles.
The interjection of NO into the equation enables the
development of a working model wherein genomic and non-
genomic influences of aldosterone become integrally depen-
dent. This concept is based on evidence that aldosterone
reduces the bioavailability of NO by a genomic-mediated
inhibition of eNOS, a conclusion reached from clinical
studies where giving spironolactone for 3 months to patients
with primary aldosteronism and high aldosterone levels
improved endothelial function (there was a more than 2-fold
greater flow-mediated dilation of the brachial artery after
treating with spironolactone).
7
Had it been possible in the
study by Schmidt et al to administer a high dose of aldoste-
rone over a longer period of time or had they included
subjects with known endothelial dysfunction, they might have
avoided the requisite for the eNOS inhibitor. In a previous
study using a dog model of obesity-induced hypertension,
both blood pressure and renal glomerular hyperfiltration
decreased after treating with eplerenone,
8
a selective MR
antagonist. This could be an instance where blocking a genomic
pathway (aldosterone-induced inhibition of NO release) pre-
vented the nongenomic pathway (aldosterones effect on the
vasculature) from developing. It should be noted that in the
chronic dog model reducing exposure to endogenous levels
of aldosterone by using eplerenone reduced the glomerular
filtration rate (GFR), whereas the opposite intervention of
giving aldosterone together with L-NMMA also resulted in a
lowering of GFR. This disparity in how aldosterone affected
GFR cannot with certainly be explained. It is likely that the
answer lies in the differences in experimental designs, with
fluid and electrolyte shifts affecting hemodynamics and
resulting in different renal affects from that observed in the
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the Department of Medicine, Indiana University School of
Medicine and the Richard L. Roudebush V.A. Medical Center, Indianap-
olis, In.
Correspondence to J. Howard Pratt, MD, R.L. Roudebush VA Medical
Center, 1481 W 10th St, Indianapolis, IN 46202. E-mail
johpratt@iupui.edu
(Hypertension. 2006;47:636-637.)
2006 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000205225.88721.2c
636
Editorial Commentary
at INDIANA UNIV SCH OF MED on March 6, 2014 http://hyper.ahajournals.org/ Downloaded from
acute setting only. The dog model of obesity-induced hyper-
tension is an example of how difficult it might be to separate
out a nongenomic effect under conditions where there are
probably multiple factors, including genomic factors that
operate to maintain the steady state.
Estrogen increases NO synthesis and bioavailability
9
lead-
ing to vasodilation and possibly contributing to the sexual
dimorphism in blood pressure (such as the lower blood
pressures in premenopausal women when compared with
age-matched men). Estrogen also has well characterized
nongenomic effects and indeed there is a recent description of
a membrane receptor that is activated by estrogen.
10
Work in
the estrogen field has led to new treatment options, namely
the synthesis of an estrogen receptor ligand that preferen-
tially activates a nongenomic pathway in bone.
11
Thus, it
would seem likely that drug development could lead to
inhibitors of nongenomic actions of aldosterone, should
the benefit of such an approach be firmly established.
There is in fact evidence that eplerenone may posses such
nongenomic properties.
12
In summary, aldosterone may have important nongenomic
vascular effects in the kidney that can ultimately influence
blood pressure. There may be buffering of the effect by NO
when the endothelium is healthy and aldosterone levels are
normal. Since aldosterone appears to decrease the bioavail-
ability of NO through a genomic mechanism, the nongenomic
mediated vascular response might be preventable with use of
currently available MR antagonists. The future may hold
promise for development of inhibitors specifically designed
to curtail nongenomic influences. The widespread prevalence
of endothelial dysfunction would seem to justify a more
intensive examination of the vascular effects of aldosterone,
studies that should include additional clinical observations.
Acknowledgments
Supported by ational Institutes of Health grants RO1-HL6730 and
RO1-HL-3579 and by the Veterans Affairs Medical Center.
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Chun and Pratt Aldosterones Nongenomic Renal Effects 637
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