Mineralocorticoid Receptor Antagonism Attenuates Cardiac Hypertrophy and Failure in Low-Aldosterone Hypertensive Rats

Abstract

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 11␤-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.

Mechanism underlying the efficacy of combination therapy with losartan and hydrochlorothiazide in rats with salt-sensitive hypertension

“…37 Cardiac fibrosis is a pathological feature associated with hypertension and cardiac hypertrophy and is responsible for LV diastolic dysfunction, likely as a result of an increase in LV stiffness. 25 In this study, LV hypertrophy and fibrosis were markedly attenuated by LOS in the presence of a moderate reduction in blood pressure, consistent with our previous results and those of others. 10,22,38 Thiazide-like diuretics have been the cornerstone of hypertension treatment for several years.…”

“…NM_022456) receptor, transforming growth factorb1 (TGF-b1) 22 or connective tissue growth factor (CTGF). 25 Reagents for detection of human 18S rRNA (Applied Biosystems) were used to quantify rat 18S rRNA as an internal standard.…”

Role of mineralocorticoid receptor on atrial structural remodeling and inducibility of atrial fibrillation in hypertensive rats

“…We confirmed that the serum concentration of aldosterone did not increase in the DS+HS group compared with that of the DS+NS group. Recent basic studies have demonstrated that MR activation is important in the etiology of cardiovascular and renal diseases not only in highaldosterone status but also in low-aldosterone hypertension, 12,36 which are consistent with our results. How is MR activated in lowaldosterone hypertension?…”

“…7,8 Recent large clinical trials, both the Randomized Aldactone Evaluation Study (RALES) and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival (EPHESUS) studies, and other animal studies have demonstrated the beneficial effects of mineralocorticoid receptor (MR) antagonists on the prognosis and ventricular remodeling. [9][10][11][12] However, little is known about the effects of the MR antagonist on atrial remodeling in hypertension. MR stimulation is linked to interstitial fibrosis, inflammation, hypertrophy and superoxide production in the heart, [13][14][15] all of which are known to provide a pathogenic substrate for AF.…”

Spironolactone Modulates Expressions of Cardiac Mineralocorticoid Receptor and 11.BETA.-Hydroxysteroid Dehydrogenase 2 and Prevents Ventricular Remodeling in Post-Infarct Rat Hearts

“…Several previous reports have demonstrated that expression of MR mRNA was significantly increased under pathological conditions, such as post-MI and heart failure (47,48). Indeed, in vitro studies have shown that aldosterone and α-adrenergic stimulation each significantly increases the expression of MR mRNA (49,50).…”