S-12-6: CARDIOPROTECTIVE EFFECTS OF FINERENONE ASSOCIATED WITH THE SUPPRESSION OF MYOCARDIAL SODIUM ACCUMULATION IN ALDOSTERONE-INDUCED RATS

Abstract

 

Recent clinical studies have indicated that the nonsteroidal mineralocorticoid receptor (MR) antagonist, finerenone, elicits significant cardioprotective effects. However, its precise mechanism is not clear. Here, we aimed to test the hypothesis that cardioprotective effects of finerenone is associated with sodium and macrophage accumulations in heart tissues. Effects of finerenone (10 mg/kg body weight by oral gavage) on myocardial injury and sodium accumulation were examined in Sprague-Dawley rats with chronic aldosterone infusion (0.75 μg/hr) and salt loading through drinking water (1% NaCl). In a survival study, we have started treatment from 6 weeks of age and found that all aldosterone-infused rats died within 30 days infusion, while all those concomitantly treated with finerenone survived until 42 days. In other experiments, we started all treatments from 7 weeks of age, and echocardiography and gene expression analyses revealed an adverse cardiac remodeling as well as diastolic dysfunction with preserved ejection fraction in rats with salt loading and aldosterone infusion for 4 weeks. Notably, finerenone treatment completely prevented the cardiac dysfunction with the improved cardiac remodeling in these rats. Furthermore, Na+ content as well as Na+/K+ ratio in left ventricular tissues were markedly elevated in salt-loaded aldosterone-infused rats, but significantly reduced in rats with concomitant finerenone treatment. Moreover, gene expression of F4/80 (a macrophage marker) was significantly reduced by finerenone treatment. These data indicate that finerenone has the potential to mitigate cardiac diastolic dysfunction in salt-loaded and aldosterone-infused rats by suppressing sodium accumulation in left ventricular tissues. These effects of finerenone may attenuate a subsequent inflammation by macrophages and adverse cardiovascular remodeling.