A Lifetime of Aldosterone Excess: Long-Term Consequences of Altered Regulation of Aldosterone Production for Cardiovascular Function
John M. C. Connell,
Scott M. MacKenzie,
E. Marie Freel,
Robert Fraser and
Eleanor Davies
Medical Research Council Blood Pressure Group, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, United Kingdom
Correspondence: Address all correspondence and requests for reprints to: Professor John M. C. Connell, Division of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, 126 University Place, Glasgow G12 8TA, United Kingdom. E-mail: jmcc1m{at}clinmed.gla.ac.uk
Up to 15% of patients with essential hypertension have inappropriateregulation of aldosterone; although only a minority have distinctadrenal tumors, recent evidence shows that mineralocorticoidreceptor activation contributes to the age-related blood pressurerise and illustrates the importance of aldosterone in determiningcardiovascular risk. Aldosterone also has a major role in progressionand outcome of ischemic heart disease. These data highlightthe need to understand better the regulation of aldosteronesynthesis and its action.
Aldosterone effects are mediated mainly through classical nuclearreceptors that alter gene transcription. In classic epithelialtarget tissues, signaling mechanisms are relatively well defined.However, aldosterone has major effects in nonepithelial tissuesthat include increased synthesis of proinflammatory moleculesand reactive oxygen species; it remains unclear how these effectsare controlled and how receptor specificity is maintained.
Variation in aldosterone production reflects interaction ofgenetic and environmental factors. Although the environmentalfactors are well understood, the genetic control of aldosteronesynthesis is still the subject of debate. Aldosterone synthase(encoded by the CYP11B2 gene) controls conversion of deoxycorticosteroneto aldosterone. Polymorphic variation in CYP11B2 is associatedwith increased risk of hypertension, but the molecular mechanismthat accounts for this is not known. Altered 11β-hydroxylaseefficiency (conversion of deoxycortisol to cortisol) as a consequenceof variation in the neighboring gene (CYP11B1) may be importantin contributing to altered control of aldosterone synthesis,so that the risk of hypertension may reflect a digenic effect,a concept that is discussed further. There is evidence thata long-term increase in aldosterone production from early lifeis determined by an interaction of genetic and environmentalfactors, leading to the eventual phenotypes of aldosterone-associatedhypertension and cardiovascular damage in middle age and beyond.
The importance of aldosterone has generated interest in itstherapeutic modulation. Disadvantages associated with spironolactone(altered libido, gynecomastia) have led to a search for alternativemineralocorticoid receptor antagonists. Of these, eplerenonehas been shown to reduce cardiovascular risk after myocardialinfarction. The benefits and disadvantages of this therapeuticapproach are discussed.
This article has been cited by other articles:
F. R. Perez-Lopez, L. Larrad-Mur, A. Kallen, P. Chedraui, and H. S. Taylor Review: Gender Differences in Cardiovascular Disease: Hormonal and Biochemical Influences
Reproductive Sciences,
June 1, 2010;
17(6):
511 - 531.
[Abstract][PDF]
A. W. Krug, L. Allenhofer, R. Monticone, G. Spinetti, M. Gekle, M. Wang, and E. G. Lakatta Elevated Mineralocorticoid Receptor Activity in Aged Rat Vascular Smooth Muscle Cells Promotes a Proinflammatory Phenotype via Extracellular Signal-Regulated Kinase 1/2 Mitogen-Activated Protein Kinase and Epidermal Growth Factor Receptor-Dependent Pathways
Hypertension,
June 1, 2010;
55(6):
1476 - 1483.
[Abstract][Full Text][PDF]
A. Tomaschitz, W. Maerz, S. Pilz, E. Ritz, H. Scharnagl, W. Renner, B. O. Boehm, A. Fahrleitner-Pammer, G. Weihrauch, and H. Dobnig Aldosterone/Renin Ratio Determines Peripheral and Central Blood Pressure Values Over a Broad Range
J. Am. Coll. Cardiol.,
May 11, 2010;
55(19):
2171 - 2180.
[Abstract][Full Text][PDF]
S. Alvarez-Madrazo, S. Padmanabhan, B. M. Mayosi, H. Watkins, P. Avery, A. M. Wallace, R. Fraser, E. Davies, B. Keavney, and J. M. Connell Familial and Phenotypic Associations of the Aldosterone Renin Ratio
J. Clin. Endocrinol. Metab.,
November 1, 2009;
94(11):
4324 - 4333.
[Abstract][Full Text][PDF]
J. B. Pippal, Y. Yao, F. M. Rogerson, and P. J. Fuller Structural and Functional Characterization of the Interdomain Interaction in the Mineralocorticoid Receptor
Mol. Endocrinol.,
September 1, 2009;
23(9):
1360 - 1370.
[Abstract][Full Text][PDF]
A. J Rickard and M. J Young Corticosteroid receptors, macrophages and cardiovascular disease
J. Mol. Endocrinol.,
June 1, 2009;
42(6):
449 - 459.
[Abstract][Full Text][PDF]
R. M. Reynolds, B. R. Walker, D. I. Phillips, E. M. Dennison, R. Fraser, S. M. Mackenzie, E. Davies, and J. M. Connell Programming of Hypertension: Associations of Plasma Aldosterone in Adult Men and Women With Birthweight, Cortisol, and Blood Pressure
Hypertension,
June 1, 2009;
53(6):
932 - 936.
[Abstract][Full Text][PDF]
J. Matrozova, O. Steichen, L. Amar, S. Zacharieva, X. Jeunemaitre, and P.-F. Plouin Fasting Plasma Glucose and Serum Lipids in Patients With Primary Aldosteronism: A Controlled Cross-Sectional Study
Hypertension,
April 1, 2009;
53(4):
605 - 610.
[Abstract][Full Text][PDF]
J. B Pippal and P. J Fuller Structure-function relationships in the mineralocorticoid receptor
J. Mol. Endocrinol.,
December 1, 2008;
41(6):
405 - 413.
[Abstract][Full Text][PDF]
