Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and failure in low-aldosterone hypertensive rats

Kohzo Nagata, Koji Obata, Jinglan Xu, Sahoko Ichihara, Akiko Noda, Hirotaka Kimata, Tomoko Kato, Hideo Izawa, Toyoaki Murohara, Mitsuhiro Yokota

Research output: Contribution to journalArticle

179 Citations (Scopus)

Abstract

Chronic elevation of plasma aldosterone contributes to heart failure. Mineralocorticoid receptor (MR) antagonism is cardioprotective in such a setting, but whether such protection occurs in the presence of low-aldosterone concentrations remains unclear. We investigated whether MR blockade attenuates cardiac hypertrophy and failure in rats with salt-sensitive hypertension. Dahl salt-sensitive (DS) rats fed a high-salt diet from 7 weeks develop concentric left ventricular (LV) hypertrophy secondary to hypertension at 12 weeks followed by heart failure at 19 weeks (DS-CHF). DS rats on such a diet were treated with a non-antihypertensive dose of the selective MR antagonist eplerenone from 12 to 19 weeks. Renin activity and aldosterone concentration in plasma were decreased in DS-CHF rats compared with controls. LV hypertrophy and fibrosis, as well as macrophage infiltration around coronary vessels, were apparent in DS-CHF rats. The amounts of mRNAs for 11β-hydroxysteroid dehydrogenase type 1, MR, monocyte chemoattractant protein 1, and osteopontin were increased in these hearts. Treatment of DS-CHF rats with eplerenone inhibited these changes in gene expression, as well as coronary vascular inflammation and heart failure. Eplerenone attenuated both the decrease in the ratio of reduced to oxidized glutathione and the increase in NADPH oxidase activity apparent in DS-CHF rat hearts. MR blockade with eplerenone thus resulted in attenuation of LV hypertrophy and failure, without an antihypertensive effect, in rats with low-aldosterone hypertension. The beneficial cardiac effects of eplerenone are likely attributable, at least in part, to attenuation of myocardial oxidative stress and coronary vascular inflammation induced by glucocorticoid-activated MRs.

Original languageEnglish
Pages (from-to)656-664
Number of pages9
JournalHypertension
Volume47
Issue number4
DOIs
Publication statusPublished - 01-04-2006
Externally publishedYes

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Inbred Dahl Rats
Mineralocorticoid Receptors
Cardiomegaly
Aldosterone
Heart Failure
Left Ventricular Hypertrophy
Salts
Hypertension
Blood Vessels
11-beta-Hydroxysteroid Dehydrogenases
Diet
Inflammation
Mineralocorticoid Receptor Antagonists
Osteopontin
Glutathione Disulfide
Chemokine CCL2
NADPH Oxidase
Renin
Antihypertensive Agents
Glucocorticoids

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

Nagata, Kohzo ; Obata, Koji ; Xu, Jinglan ; Ichihara, Sahoko ; Noda, Akiko ; Kimata, Hirotaka ; Kato, Tomoko ; Izawa, Hideo ; Murohara, Toyoaki ; Yokota, Mitsuhiro. / Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and failure in low-aldosterone hypertensive rats. In: Hypertension. 2006 ; Vol. 47, No. 4. pp. 656-664.
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Nagata, K, Obata, K, Xu, J, Ichihara, S, Noda, A, Kimata, H, Kato, T, Izawa, H, Murohara, T & Yokota, M 2006, 'Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and failure in low-aldosterone hypertensive rats', Hypertension, vol. 47, no. 4, pp. 656-664. https://doi.org/10.1161/01.HYP.0000203772.78696.67

Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and failure in low-aldosterone hypertensive rats. / Nagata, Kohzo; Obata, Koji; Xu, Jinglan; Ichihara, Sahoko; Noda, Akiko; Kimata, Hirotaka; Kato, Tomoko; Izawa, Hideo; Murohara, Toyoaki; Yokota, Mitsuhiro.

In: Hypertension, Vol. 47, No. 4, 01.04.2006, p. 656-664.

Research output: Contribution to journalArticle

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T1 - Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and failure in low-aldosterone hypertensive rats

AU - Nagata, Kohzo

AU - Obata, Koji

AU - Xu, Jinglan

AU - Ichihara, Sahoko

AU - Noda, Akiko

AU - Kimata, Hirotaka

AU - Kato, Tomoko

AU - Izawa, Hideo

AU - Murohara, Toyoaki

AU - Yokota, Mitsuhiro

PY - 2006/4/1

Y1 - 2006/4/1

N2 - Chronic elevation of plasma aldosterone contributes to heart failure. Mineralocorticoid receptor (MR) antagonism is cardioprotective in such a setting, but whether such protection occurs in the presence of low-aldosterone concentrations remains unclear. We investigated whether MR blockade attenuates cardiac hypertrophy and failure in rats with salt-sensitive hypertension. Dahl salt-sensitive (DS) rats fed a high-salt diet from 7 weeks develop concentric left ventricular (LV) hypertrophy secondary to hypertension at 12 weeks followed by heart failure at 19 weeks (DS-CHF). DS rats on such a diet were treated with a non-antihypertensive dose of the selective MR antagonist eplerenone from 12 to 19 weeks. Renin activity and aldosterone concentration in plasma were decreased in DS-CHF rats compared with controls. LV hypertrophy and fibrosis, as well as macrophage infiltration around coronary vessels, were apparent in DS-CHF rats. The amounts of mRNAs for 11β-hydroxysteroid dehydrogenase type 1, MR, monocyte chemoattractant protein 1, and osteopontin were increased in these hearts. Treatment of DS-CHF rats with eplerenone inhibited these changes in gene expression, as well as coronary vascular inflammation and heart failure. Eplerenone attenuated both the decrease in the ratio of reduced to oxidized glutathione and the increase in NADPH oxidase activity apparent in DS-CHF rat hearts. MR blockade with eplerenone thus resulted in attenuation of LV hypertrophy and failure, without an antihypertensive effect, in rats with low-aldosterone hypertension. The beneficial cardiac effects of eplerenone are likely attributable, at least in part, to attenuation of myocardial oxidative stress and coronary vascular inflammation induced by glucocorticoid-activated MRs.

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