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

Abstract

Hypertension is well known to increase atrial fibrillation (AF) and the development of AF is associated with atrial chamber remodeling. Although mineralocorticoid receptor (MR) inhibition provides cardiovascular protection, the role of MR on atrial structural remodeling and inducibility of AF in hypertension remains unclear. Here, we investigated roles of the MR on atrial structural remodeling and inducibility of AF in hypertensive rats by using MR antagonist eplerenone (EPL). Dahl salt-sensitive (DS) rats were fed a normal-salt or a high-salt (HS) diet from 7 weeks, and a non-antihypertensive dose of EPL or vehicle was administrated from 13 weeks, at which time myocytes hypertrophy, interstitial fibrosis in the atrium and AF inducibility had increased, until 20 weeks. There was no significant difference in systolic blood pressure between DS+HS (186±4 mm Hg) and DS+HS+EPL (184±5 mm Hg) at 20 weeks. Burst atrial pacing demonstrated decreased AF inducibility in DS+HS+EPL (0 of 10) compared with DS+HS (7 of 10). Fibrosis and myocytes hypertrophy in the atrium were decreased in DS+HS+EPL with the reduction of atrial inflammatory cytokines. These beneficial effects of EPL were associated with less atrial oxidative stress, as assessed by 4-hydroxy-2-nonenal staining, and reduced activation of the Rho GTPase Rac1 in the atrium. Thus, MR has important roles in atrial structural remodeling and AF inducibility in Dahl rats. The effects of MR are associated, at least in part, with activation of Rac1-oxidative stress/inflammatory axis.

Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats

“…4,5 The beneficial effects of the MR antagonist spironolactone or the more specific antagonist eplerenone on end-organ damage have been studied in animal models. [6][7][8][9][10] It has been reported that MRs regulate epithelial Na channels (ENaCs) that are important for the regulation of sodium transport and the maintenance of extracellular fluid volume and arterial pressure (AP) in the kidney. 11 Recent studies have reported the distribution of MRs or ENaCs in the choroid plexus, ependyma and neurons, such as those in the supraoptic nucleus, paraventricular nucleus and nucleus tractus solitarius.…”

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

“…Spironolactone prevents atrial remodeling (fibrosis and dilation) as well as apoptosis in an experimental model of atrial fibrillation (AF) and prevents the increased inducibility and duration of tachypacinginduced AF (Zhao et al, 2010a) as well as atrial remodeling and AF inducibility in a rat hypertensive model (Kimura et al, 2011). Fibrotic remodeling observed in a genetic mouse model of AF (constitutively active Rac1 under the control of the a myosin heavy chain) is prevented by MR antagonism (spironolactone or nonsteroidal BR-4628) (Lavall et al, 2014).…”

Spironolactone for Management of Heart Failure with Preserved Ejection Fraction: Whither to After TOPCAT?

“…Comorbid HFpEF conditions, including diabetes mellitus, hypertension, obesity, and chronic kidney disease, similarly lead to increased oxidative stress and impaired vascular compliance and endothelial function [20,21]. At a cellular level, aldosterone antagonism decreases oxidative stress and collagen deposition and improves vascular compliance and myocardial perfusion [28][29][30][31][32]. Clinically, MRAs have proven quite efficacious in reducing mortality in HFrEF patients with New York Heart Association (NYHA) class II to IV symptoms [33,34].…”