Ménard, Joël, Watson, Catherine, Rigel, Dean, Jeng, Arco Y., Liang, Guiqing, Rebello, Sam, Zhang, Yiming, Dole, William, Fu, Fumin, Beil, Michael, Liu, Jing, Chen, Wei, Hu, Chii-Whei, Leung-Chu, Jennifer and LaSala, Daniel (2015) Aldosterone synthase inhibition: cardiorenal protection in animal disease models and translation of hormonal effects to human subjects. Journal of Translational Medicine.

Abstract

Aldosterone synthase inhibition provides the potential to attenuate both the mineralocorticoid receptor dependent and independent actions of aldosterone. This is the first report of the effects of pharmacologic inhibition of aldosterone synthase in normal human subjects. In vitro studies with recombinant human enzymes showed that LCI699 is a potent, reversible, competitive inhibitor of aldosterone synthase (Ki = 1.4 ± 0.2 nmol/L in humans) with relative selectivity over 11β-hydroxylase. Rat and monkey in vivo models of adrenocorticotropic hormone and angiotensin II-stimulated aldosterone synthesis predicted human dose– and exposure-response relationships, but overestimated the selectivity of LCI699 in humans. In a double-transgenic rat model overexpressing human renin and angiotensinogen, LCI699 dose-dependently blocked increases in aldosterone, prevented development of cardiac and renal functional abnormalities independent of blood pressure changes, and prolonged survival. In a randomized, placebo-controlled study in healthy humans, LCI699 0.5 mg selectively reduced plasma and urinary aldosterone (49% and 40%, respectively), which was associated with natriuresis and an increase in plasma renin activity. In contrast to LCI699, the selective mineralocorticoid receptor antagonist eplerenone 100 mg increased plasma and urinary aldosterone (71% and 18%, respectively) while stimulating comparable natriuresis and changes in renin activity compared to LCI699. LCI699 increased the aldosterone precursor 11-deoxycorticosterone, and in contrast to eplerenone, increased urinary potassium excretion. These results provide new insights into the effects of inhibiting aldosterone synthase in experimental models and the translation of their short-term hormonal effects to humans, and provide further therapeutic rationale for targeting inhibition of aldosterone synthase to treat diseases associated with aldosterone excess.

Item Type:	Article
Keywords:	N/A
Date Deposited:	13 Oct 2015 13:15
Last Modified:	13 Oct 2015 13:15
URI:	https://oak.novartis.com/id/eprint/4357