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).