title: Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and failure in low-aldosterone hypertensive rats.
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 11beta-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.
authors.affiliation: Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan. nagata@met.nagoya-u.ac.jp
authors.forename: Kohzo
authors.initials: K
authors.lastname: Nagata
authors.forename: Koji
authors.initials: K
authors.lastname: Obata
authors.forename: Jinglan
authors.initials: J
authors.lastname: Xu
authors.forename: Sahoko
authors.initials: S
authors.lastname: Ichihara
authors.forename: Akiko
authors.initials: A
authors.lastname: Noda
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kimata
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kato
authors.forename: Hideo
authors.initials: H
authors.lastname: Izawa
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yokota
mesh_terms: D000450:Aldosterone / Q000097:blood*; D000818:Animals; D002303:Cardiac Output, Low / Q000209:etiology / Q000503:physiopathology*; D006332:Cardiomegaly / Q000000981:diagnostic imaging* / Q000209:etiology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003331:Coronary Vessels; D003345:Corticosterone / Q000097:blood; D004452:Echocardiography; D000077545:Eplerenone; D006973:Hypertension / Q000097:blood / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D009206:Myocardium / Q000378:metabolism; D009994:Osmolar Concentration; D018384:Oxidative Stress / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D012083:Renin / Q000097:blood; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D014657:Vasculitis / Q000209:etiology; D016276:Ventricular Function; D020257:Ventricular Remodeling
chemical_list: D002316:Cardiotonic Agents; D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D003345:Corticosterone