Cardioprotective Effects of a Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, in Dahl Salt-Sensitive Hypertensive Rats

Abstract

We investigated the effects of esaxerenone, a novel, nonsteroidal, and selective mineralocorticoid receptor blocker, on cardiac function in Dahl salt-sensitive (DSS) rats. We provided 6-week-old DSS rats a high-salt diet (HSD, 8% NaCl). Following six weeks of HSD feeding (establishment of cardiac hypertrophy), we divided the animals into the following two groups: HSD or HSD + esaxerenone (0.001%, w/w). In survival study, all HSD-fed animals died by 24 weeks of age, whereas the esaxerenone-treated HSD-fed animals showed significantly improved survival. We used the same protocol with a separate set of animals to evaluate the cardiac function by echocardiography after four weeks of treatment. The results showed that HSD-fed animals developed cardiac dysfunction as evidenced by reduced stroke volume, ejection fraction, and cardiac output. Importantly, esaxerenone treatment decreased the worsening of cardiac dysfunction concomitant with a significantly reduced level of systolic blood pressure. In addition, treatment with esaxerenone in HSD-fed DSS rats caused a reduced level of cardiac remodeling as well as fibrosis. Furthermore, inflammation and oxidative stress were significantly reduced. These data indicate that esaxerenone has the potential to mitigate cardiac dysfunction in salt-induced myocardial injury in rats.

Characterization of Direct Perturbations on Voltage-Gated Sodium Current by Esaxerenone, a Nonsteroidal Mineralocorticoid Receptor Blocker

“…In concert with its antagonistic action on MR, ESAX might exert an additional ameliorating action on salt-induced elevation of blood pressure or on kidney injuries [ 1 , 6 , 8 , 10 , 41 , 42 ]. ESAX has indeed reported the ability of alleviating effects in hypertensive patients with normal kidney function and in diabetic patients with albuminuria [ 5 ].…”

“…Esaxerenone (ESAX; Minnebro ® , CS-3150, XL-560, Oklahoma, Japan), known to be a newly oral, non-steroidal selective blocker on the activity of mineralocorticoid receptor (MR), has been growingly used for the management of varying pathologic disorders, such as primary aldosteronism, refractory hypertension, chronic kidney disease, diabetic nephropathy, and heart failure [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. Alternatively, the activity of MR has been previously reported in pituitary cells including GH 3 cells or in varying brain regions [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

Implication of Mineralocorticoid Receptor Antagonist Esaxerenone in Patients With Heart Failure With Preserved Ejection Fraction

“…Logistic regression analyses were used to investigate factors associated with a >30 g/m 2 decrease in LVMI during esaxerenone therapy, which was defined as the cut-off for appropriate reverse remodeling according to a previous study. 11 Variables with P<0.05 were included in the multivariate analysis.…”

Association of Antihypertensive Effects of Esaxerenone with the Internal Sodium Balance in Dahl Salt-Sensitive Hypertensive Rats

“…An elevation in BP with an altered dipping pattern in response to high dietary salt intake is a characteristic phenomenon of SSH, which enhances cardiorenal morbidity and mortality [ 6 ]. We previously showed the antihypertensive effects of a nonsteroidal mineralocorticoid receptor blocker, esaxerenone, in DSS rats [ 21 ]. In this study, we examined the effects of esaxerenone and furosemide on the diurnal variation in BP, as well as the associated possible underlying mechanism.…”

“…Importantly, esaxerenone is effective in reducing BP in patients with hypertension [ 19 , 20 ]. In the context of SSH, our research team and others have shown that esaxerenone treatment significantly reduces BP and cardiorenal injury in high salt (HS)-loaded Dahl salt-sensitive hypertensive (DSS) rats [ 21 , 22 , 23 ]. Furthermore, 2-week administration of esaxerenone (3 mg/kg/day) significantly reduced BP in deoxycorticosterone acetate/salt-loaded rats compared with their control counterparts, but not in those with eplerenone and spironolactone loading (30 mg/kg/day) [ 24 ].…”