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

被引:204
作者
Nagata, K
Obata, K
Xu, JL
Ichihara, S
Noda, A
Kimata, H
Kato, T
Izawa, H
Murohara, T
Yokota, M
机构
[1] Nagoya Univ, Sch Hlth Sci, Dept Med Technol, Higashi Ku, Nagoya, Aichi 4618673, Japan
[2] Nagoya Univ, Sch Med, Dept Cardiovasc Genome Sci, Nagoya, Aichi 4618673, Japan
[3] Mie Univ, Life Sci Res Ctr, Tsu, Mie, Japan
[4] Nagoya Univ, Grad Sch Med, Dept Cardiol, Nagoya, Aichi, Japan
关键词
hypertension; sodium-dependent; hypertrophy; fibrosis; heart failure; mineralocorticoids; glucocorticoids; oxidative stress;
D O I
10.1161/01.HYP.0000203772.78696.67
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
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 11 beta-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.
引用
收藏
页码:656 / 664
页数:9
相关论文
共 38 条
[21]   Aldosterone directly stimulates cardiac myocyte hypertrophy [J].
Okoshi, MP ;
Yan, XH ;
Okoshi, K ;
Nakayama, M ;
Schuldt, AJT ;
O'Connell, TD ;
Simpson, PC ;
Lorell, BH .
JOURNAL OF CARDIAC FAILURE, 2004, 10 (06) :511-518
[22]   Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction [J].
Pitt, B ;
Remme, W ;
Zannad, F ;
Neaton, J ;
Martinez, F ;
Roniker, B ;
Bittman, R ;
Hurley, S ;
Kleiman, J ;
Gatlin, M .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 348 (14) :1309-1321
[23]   Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy - The 4E-left ventricular hypertrophy study [J].
Pitt, B ;
Reichek, N ;
Willenbrock, R ;
Zannad, F ;
Phillips, RA ;
Roniker, B ;
Kleiman, J ;
Krause, S ;
Burns, D ;
Williams, GH .
CIRCULATION, 2003, 108 (15) :1831-1838
[24]   The effect of spironolactone on morbidity and mortality in patients with severe heart failure [J].
Pitt, B ;
Zannad, F ;
Remme, WJ ;
Cody, R ;
Castaigne, A ;
Perez, A ;
Palensky, J ;
Wittes, J .
NEW ENGLAND JOURNAL OF MEDICINE, 1999, 341 (10) :709-717
[25]   Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure [J].
Qin, WN ;
Rudolph, AE ;
Bond, BR ;
Rocha, R ;
Blomme, EAG ;
Goellner, JJ ;
Funder, JW ;
McMahon, EG .
CIRCULATION RESEARCH, 2003, 93 (01) :69-76
[26]   Hypertension and the cortisol-cortisone shuttle [J].
Quinkler, M ;
Stewart, PM .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2003, 88 (06) :2384-2392
[27]   Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation - Contribution to alterations of vasomotor tone [J].
Rajagopalan, S ;
Kurz, S ;
Munzel, T ;
Tarpey, M ;
Freeman, BA ;
Griendling, KK ;
Harrison, DG .
JOURNAL OF CLINICAL INVESTIGATION, 1996, 97 (08) :1916-1923
[28]   Pathophysiological effects of aldosterone in cardiovascular tissues [J].
Rocha, R ;
Stier, CT .
TRENDS IN ENDOCRINOLOGY AND METABOLISM, 2001, 12 (07) :308-314
[29]   Aldosterone induces a vascular inflammatory phenotype in the rat heart [J].
Rocha, R ;
Rudolph, AE ;
Frierdich, GE ;
Nachowiak, DA ;
Kekec, BK ;
Blomme, EAG ;
McMahon, EG ;
Delyani, JA .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2002, 283 (05) :H1802-H1810
[30]   Connective tissue growth factor is a mediator of angiotensin II-induced fibrosis [J].
Rupérez, M ;
Lorenzo, O ;
Blanco-Colio, LM ;
Esteban, V ;
Egido, J ;
Ruiz-Ortega, M .
CIRCULATION, 2003, 108 (12) :1499-1505