Hypertensive models
MRAs have been widely used in hypertensive models, highlighting its beneficial effects in CV fibrosis, oxidative stress and inflammation. These experimental models include aldosterone-salt, deoxycorticosterone acetate (DOCA)-salt or angiotensin II treatments, thoracic aortic constriction or spontaneously hypertensive rats. The vast majority of studies have been conducted in aldosterone-salt-challenged animals co-treated with MRA and have focused on adverse vascular and cardiac remodeling and dysfunction. Increased oxidative stress and vascular inflammation are the first effects of aldosterone in vessels, being vascular inflammation partly dependent on oxidative stress (Sun et al., 2002).
Spironolactone prevented aldosterone-salt-induced oxidative stress as well as vascular infiltration of monocytes, macrophages, and lymphocytes in mice (Kasal et al., 2012) and rats (Nakano et al., 2005). Regarding vascular function, eplerenone blunted the aldosterone-induced increase in large artery stiffness, pulse pressure and the carotid elastic modulus (Lacolley et al., 2002). Spironolactone reduced cardiac inflammation and oxidative stress induced by aldosterone treatment (Sun et al., 2002) and eplerenone prevented aldosterone-dependent cardiac fibrosis (Nebme et al., 2006).
Spironolactone decreased cardiac fibrosis by blocking the activation of T Helper 17 and the downregulation of regulatory T lymphocytes in DOCA-salt rats (Amador et al., 2014), suggesting that T cells could be involved in aldosterone-induced oxidative stress, because DOCA acts through MR (Guzik et al., 2007).
In angiotensin II-dependent models, spironolactone improved vascular changes and oxidative stress (Virdis et al., 2002), and blocked the hypertensive effects as well as the cardiac fibrosis and oxidative stress (Johar et al., 2006). Using angiotensin II overproducing transgenic mice, the protective effect of spironolactone against hypertensive vascular hypertrophy and remodeling has also been proved (Sakurabayashi-Kitade et al., 2009).
In line with these findings, eplerenone decreased myocardial oxidative stress, fibrosis and inflammation, limiting the transition to HF in a pressure-overload mice model (Kuster et al., 2005). In spontaneously hypertensive rats, early spironolactone treatment also decreased HF development by improving myocardial systolic and diastolic function, and attenuating hypertrophy and fibrosis (Cezar et al., 2015).
Treatment with spironolactone also prevented diet-induced diastolic dysfunction and arterial stiffness in female mice (De Marco et al., 2015). Finerenone improved HFpEF by decreasing LV filling pressure, increasing LV compliance, and prevented coronary endothelial dysfunction in ovariectomized mice (Pieronne-Deperrois et al., 2021).