Aldosterone Synthase Inhibition: Cardiorenal Protection in Animal Disease Models and Translation of Hormonal Effects to Human Subjects


Hormonal effects of orally administered LCI699 were examined in rat and monkey in vivo models of adrenocorticotropic hormone (ACTH) and angiotensin-II-stimulated aldosterone release, and were compared with the mineralocorticoid receptor antagonist eplerenone in a randomized, placebo-controlled study conducted in 99 healthy human subjects. The effects of LCI699 and eplerenone on cardiac and renal sequelae of aldosterone excess were investigated in a double-transgenic rat (dTG rat) model overexpressing human renin and angiotensinogen. In healthy human subjects, LCI699 0.5 mg selectively reduced plasma and 24 h urinary aldosterone by 49 ± 3% and 39 ± 6% respectively (Day 1, mean ± SEM; P < 0.001 vs placebo), which was associated with natriuresis and an increase in plasma renin activity. Doses of LCI699 greater than 1 mg inhibited basal and ACTH-stimulated cortisol. Eplerenone 100 mg increased plasma and 24 h urinary aldosterone while stimulating natriuresis and increasing renin activity. In contrast to eplerenone, LCI699 increased the aldosterone precursor 11-deoxycorticosterone and urinary potassium excretion.

Authors: Joël Ménard, Dean F Rigel, Catherine Watson, Arco Y Jeng, Fumin Fu, Michael Beil, Jing Liu, Wei Chen, Chii-Whei Hu, Jennifer Leung-Chu, Daniel LaSala, Guiqing Liang, Sam Rebello, Yiming Zhang, William P Dole
Keywords: cytochrome P-450 CYP11B2, imidazoles, pyridines
DOI Number: 10.1186/s12967-014-0340-9      Publication Year: 2014

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