Role of Aldosterone Blockade in Heart Failure

Pitt, Bertram

doi:10.1016/j.hfc.2004.12.003

Cited by 1 publication

(1 citation statement)

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“…Within the last 10 years, blocking its effects with MR antagonists has been shown to have beneficial effects in congestive heart failure, especially after myocardial infarction, and proteinuric nephropathies. 28,29 Although our results need to be replicated in larger cohorts well phenotyped for BP and the renin-angiotensin-aldosterone axis, our data suggest that functional variants of the MR may be associated not only with different cellular responses to aldosterone but also, indirectly, with increased aldosterone levels that may activate both genomic and nongenomic pathways in nonepithelial target tissues to promote deleterious cardiovascular effects.…”

Section: Van Leeuwen Et Al Mr Polymorphism and Blood Pressure Regulationmentioning

confidence: 73%

The Functional c.-2G>C Variant of the Mineralocorticoid Receptor Modulates Blood Pressure, Renin, and Aldosterone Levels

et al. 2010

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Abstract-The mineralocorticoid receptor (MR) is essential in the regulation of volemia and blood pressure. Rare mutations in the MR gene cause type 1 pseudohypoaldosteronism and hypertension. In this study we characterized the common MR polymorphism c.-2GϾC (rs2070951) in vitro and tested its influence on parameters related to blood pressure regulation and the renin-angiotensin system. In vitro studies showed that the G allele was associated with decreased MR protein levels and reduced transcriptional activation compared with the C allele. Association studies were performed with several outcome variables in 3 independent cohorts: a mild hypertensive group subjected to a salt-sensitivity test, a healthy normotensive group included in a crossover study to receive both a high and low Na/K diet, and a large cohort (The Netherlands Study of Depression and Anxiety), in which blood pressure was measured. Subjects with the GG genotype had significantly higher plasma renin levels both in the mild hypertensive group and in normal volunteers compared with homozygous C carriers. The GG genotype was also correlated with higher plasma aldosterone levels in healthy subjects. In both the mild hypertensive group and The Netherlands Study of Depression and Anxiety cohort the genotype GG was associated with higher systolic blood pressure in males. In conclusion, the G allele of the common functional genetic polymorphism c.-2GϾC in the MR gene associates with increased activation of the renin-angiotensin-aldosterone axis and with increased blood pressure, probably related to decreased MR expression. (Hypertension. 2010;56:995-1002.)Key Words: mineralocorticoid Ⅲ aldosterone Ⅲ hypertension Ⅲ nuclear receptor Ⅲ sodium balance T he mineralocorticoid receptor (MR) mediates aldosterone effects on electrolyte balance and blood pressure (BP). Classical MR-expressing tissues include the distal parts of the nephron, colon, salivary glands, and sweat glands, where MR regulates transepithelial sodium transport. However, MRs are also expressed in nonepithelial tissues, including the cardiovascular system and the central nervous system; in these tissues, glucocorticoids represent the predominant endogenous ligand. 1 The MR belongs to the nuclear receptor superfamily and acts as a ligand-activated transcription factor regulating expression of a coordinate set of genes ultimately eliciting physiological aldosterone and cortisol responses. The gene coding for the human MR, NR3C2, is composed of 10 exons and spans over Ϸ400 kb. By means of alternative promoter use, alternative splicing, use of different translational start sites, and genetic polymorphisms, considerable variability in MR function has been observed. 2,3 Sodium handling is highly variable between individuals, and genetic factors are involved in the development of hypertension. 4 Rare mutations of the MR are responsible for mendelian disorders of renal salt handling associated with high or low BP. Loss of function mutations of the MR lead to

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Section: Van Leeuwen Et Al Mr Polymorphism and Blood Pressure Regulationmentioning

confidence: 73%