bay-94-8862 and Cardiomegaly

Pharmacological blockade of mineralocorticoid receptors (MR) is known as an efficacious therapy in chronic heart failure. Therapy with steroidal MR antagonists such as spironolactone or eplerenone (EPL) is often limited because of side effects. Recently, a new highly selective and potent, nonsteroidal MR antagonist, finerenone (FIN), has been developed. To investigate the effects of FIN on pressure-induced cardiac hypertrophy, the transverse aortic constriction (TAC) model was used in C57BL/6 mice treated with FIN (10 mg·kg·d), EPL (200 mg·kg·d) or vehicle (VEH). First, we analyzed cardiac gene expression 4 weeks after TAC using a pathway-focused quantitative polymerase chain reaction array. FIN caused a distinct cardiac gene expression profile compared to VEH and EPL, including differential expression of BNP (brain natriuretic peptide) and Tnnt2 (troponin T type 2). FIN treatment led to a significant reduction of TAC-induced left ventricular (LV) wall thickening assessed by echocardiography. In accordance, FIN-treated mice showed a significant lower increase of calculated left ventricular mass compared with VEH- and EPL-treated mice (FIN: 28.4 ± 3.7 mg; EPL: 38.4 ± 4.3 mg; VEH: 39.3 ± 3.1 mg; P < 0.05). These data show beneficial effects of nonsteroidal MR antagonism by FIN on left ventricular mass development in pressure overload associated with a distinct cardiac gene expression profile.

Topics: Animals; Cardiomegaly; Disease Models, Animal; Eplerenone; Gene Expression; Male; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Naphthyridines; Natriuretic Peptide, Brain; Spironolactone; Troponin T; Ventricular Remodeling

Pharmacological blockade of the mineralocorticoid receptor (MR) ameliorates end-organ damage in chronic heart failure. However, the clinical use of available steroidal MR antagonists is restricted because of concomitant hyperkalemia especially in patients with diminished kidney function. We have recently identified a novel nonsteroidal MR antagonist, finerenone, which uniquely combines potency and selectivity toward MR. Here, we investigated the tissue distribution and chronic cardiorenal end-organ protection of finerenone in comparison to the steroidal MR antagonist, eplerenone, in 2 different preclinical rat disease models. Quantitative whole-body autoradiography revealed that [C]-labeled finerenone equally distributes into rat cardiac and renal tissues. Finerenone treatment prevented deoxycorticosterone acetate-/salt-challenged rats from functional as well as structural heart and kidney damage at dosages not reducing systemic blood pressure. Finerenone reduced cardiac hypertrophy, plasma prohormone of brain natriuretic peptide, and proteinuria more efficiently than eplerenone when comparing equinatriuretic doses. In rats that developed chronic heart failure after coronary artery ligation, finerenone (1 mg·kg·d), but not eplerenone (100 mg·kg·d) improved systolic and diastolic left ventricular function and reduced plasma prohormone of brain natriuretic peptide levels. We conclude that finerenone may offer end-organ protection with a reduced risk of electrolyte disturbances.

Topics: Animals; Autoradiography; Cardiomegaly; Disease Models, Animal; Eplerenone; Heart Failure; Kidney Diseases; Male; Mineralocorticoid Receptor Antagonists; Naphthyridines; Natriuretic Peptide, Brain; Peptide Fragments; Rats; Rats, Sprague-Dawley; Rats, Wistar; Spironolactone; Tissue Distribution