Tae-Yon Chun and J. Howard PrattNongenomic Renal Effects of Aldosterone: Dependency on NO and Genomic Actions

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Nongenomic Renal Effects of AldosteroneDependency on NO and Genomic Actions

Tae-Yon Chun, J. Howard Pratt

There is increasing evidence for a dependency onaldosterone in the development of hypertension.1 Howaldosterone 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 thebinding of aldosterone to the classical mineralocorticoidreceptor (MR) and ends with sodium reabsorption at the distalnephron. But aldosterone can convey nongenomic influencesas well, actions that have received less attention, possibly inpart because they seem counterintuitive to our genomic view ofbiology. Adding to the complexity of aldosterone’s actions isthe fact that there are also nonepithelial (nondistal nephron)targets of aldosterone, such as the heart, the vasculature, thekidney, and other sites. In this issue of Hypertension, Schmidtet al2 describe a rapid (thus nongenomic) effect of adminis-tered aldosterone to increase resistance in renal vasculature (anonepithelial target) in healthy human subjects. The findingsfollow on the heels of a rather large body of work on thegenomic actions of aldosterone.

Aldosterone’s nongenomic effects were first recognizedmore than a decade before an aldosterone-inducible gene wasidentified in the late 1990s.3 A nongenomic action character-istically occurs almost immediately, usually within severalminutes,4 before sufficient time has elapsed for gene tran-scription and synthesis of new protein (the time it takesaldosterone 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 ismembrane associated. A role for the classical MR has notbeen ruled out5 although the MR antagonist, spironolactone,is not usually inhibitory nor is the response lost in MRknockout mice. Nongenomic responses elicited by aldoste-rone are accompanied by activation of early signal transduc-tion pathways with increases in intracellular calcium, inositoltriphosphate, diacylglycerol, and cAMP together with activa-tion of protein kinase C. Most previous nongenomic studiesof aldosterone were carried out in vitro or ex vivo, thus

limiting the chance for observing potential interactions withother 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 vasculatureoccurred 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 thatthis necessary manipulation made conditions too pharmaco-logical, it can just as easily be viewed as a replication of theendothelial dysfunction that is associated with increased riskfor cardiovascular disease, as might occur, for example, inpatients with the metabolic syndrome. Indeed, the requisitefor eNOS inhibition suggests that certain nongenomic vascu-lar effects of aldosterone become manifest only when there isa loss of endothelial integrity. This was nicely demonstratedin earlier studies carried out by Arima et al6 using isolatedrenal arterioles.

The interjection of NO into the equation enables thedevelopment of a working model wherein genomic and non-genomic influences of aldosterone become integrally depen-dent. This concept is based on evidence that aldosteronereduces the bioavailability of NO by a genomic-mediatedinhibition of eNOS, a conclusion reached from clinicalstudies where giving spironolactone for 3 months to patientswith primary aldosteronism and high aldosterone levelsimproved endothelial function (there was a more than 2-foldgreater flow-mediated dilation of the brachial artery aftertreating with spironolactone).7 Had it been possible in thestudy by Schmidt et al to administer a high dose of aldoste-rone over a longer period of time or had they includedsubjects with known endothelial dysfunction, they might haveavoided the requisite for the eNOS inhibitor. In a previousstudy using a dog model of obesity-induced hypertension,both blood pressure and renal glomerular hyperfiltrationdecreased after treating with eplerenone,8 a selective MRantagonist. This could be an instance where blocking a genomicpathway (aldosterone-induced inhibition of NO release) pre-vented the nongenomic pathway (aldosterone’s effect on thevasculature) from developing. It should be noted that in thechronic dog model reducing exposure to endogenous levelsof aldosterone by using eplerenone reduced the glomerularfiltration rate (GFR), whereas the opposite intervention ofgiving aldosterone together with L-NMMA also resulted in alowering of GFR. This disparity in how aldosterone affectedGFR cannot with certainly be explained. It is likely that theanswer lies in the differences in experimental designs, withfluid and electrolyte shifts affecting hemodynamics andresulting in different renal affects from that observed in the

The opinions expressed in this editorial are not necessarily those of theeditors or of the American Heart Association.

From the Department of Medicine, Indiana University School ofMedicine and the Richard L. Roudebush V.A. Medical Center, Indianap-olis, In.

Correspondence to J. Howard Pratt, MD, R.L. Roudebush VA MedicalCenter, 1481 W 10th St, Indianapolis, IN 46202. E-mailjohpratt@iupui.edu

(Hypertension. 2006;47:636-637.)© 2006 American Heart Association, Inc.

Hypertension is available at http://www.hypertensionaha.orgDOI: 10.1161/01.HYP.0000205225.88721.2c

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Editorial Commentary

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acute setting only. The dog model of obesity-induced hyper-tension is an example of how difficult it might be to separateout a nongenomic effect under conditions where there areprobably multiple factors, including genomic factors thatoperate to maintain the steady state.

Estrogen increases NO synthesis and bioavailability9 lead-ing to vasodilation and possibly contributing to the sexualdimorphism in blood pressure (such as the lower bloodpressures in premenopausal women when compared withage-matched men). Estrogen also has well characterizednongenomic effects and indeed there is a recent description ofa membrane receptor that is activated by estrogen.10 Work inthe estrogen field has led to new treatment options, namelythe synthesis of an estrogen receptor ligand that preferen-tially activates a nongenomic pathway in bone.11 Thus, itwould seem likely that drug development could lead toinhibitors of nongenomic actions of aldosterone, shouldthe benefit of such an approach be firmly established.There is in fact evidence that eplerenone may posses suchnongenomic properties.12

In summary, aldosterone may have important nongenomicvascular effects in the kidney that can ultimately influenceblood pressure. There may be buffering of the effect by NOwhen the endothelium is healthy and aldosterone levels arenormal. Since aldosterone appears to decrease the bioavail-ability of NO through a genomic mechanism, the nongenomicmediated vascular response might be preventable with use ofcurrently available MR antagonists. The future may holdpromise for development of inhibitors specifically designedto curtail nongenomic influences. The widespread prevalenceof endothelial dysfunction would seem to justify a moreintensive examination of the vascular effects of aldosterone,studies that should include additional clinical observations.

AcknowledgmentsSupported by ational Institutes of Health grants RO1-HL6730 andRO1-HL-3579 and by the Veterans Affairs Medical Center.

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