Abstract
BackgroundAldosterone synthase inhibition provides the potential to attenuate both the mineralocorticoid receptor-dependent and independent actions of aldosterone. In vitro studies with recombinant human enzymes showed LCI699 to be a potent, reversible, competitive inhibitor of aldosterone synthase (Ki = 1.4 ± 0.2 nmol/L in humans) with relative selectivity over 11β-hydroxylase.MethodsHormonal 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.ResultsRat and monkey in vivo models of stimulated aldosterone release predicted human dose– and exposure–response relationships, but overestimated the selectivity of LCI699 in humans. In the dTG rat model, LCI699 dose-dependently blocked increases in aldosterone, prevented development of cardiac and renal functional abnormalities independent of blood pressure changes, and prolonged survival. Eplerenone prolonged survival to a similar extent, but was less effective in preventing cardiac and renal damage. 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.ConclusionsThese results provide new insights into the cardiac and renal effects of inhibiting aldosterone synthase in experimental models and translation of the hormonal effects to humans. Selective inhibition of aldosterone synthase appears to be a promising approach to treat diseases associated with aldosterone excess.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-014-0340-9) contains supplementary material, which is available to authorized users.
Highlights
Aldosterone synthase inhibition provides the potential to attenuate both the mineralocorticoid receptor-dependent and independent actions of aldosterone
In vitro enzyme inhibition LCI699 dose-dependently inhibited the activity of recombinant human aldosterone synthase (IC50 = 0.7 nmol/L) with 3.6-fold selectivity over 11β-hydroxylase (IC50 = 2.5 nmol/L) (Table 1)
In vitro enzymatic studies using rat recombinant enzymes showed that LCI699 was approximately 230-fold less potent at inhibiting rat aldosterone synthase than the human enzyme (Table 1)
Summary
Aldosterone synthase inhibition provides the potential to attenuate both the mineralocorticoid receptor-dependent and independent actions of aldosterone. Experimental data have shown that aldosterone can cause cardiac, renal and vascular damage independent of its effects on blood pressure [2] These experimental data together with growing clinical evidence for the benefits of blocking the actions of aldosterone with mineralocorticoid receptor antagonists (MRAs) in the treatment of heart failure [3,4,5] provide the rationale for new therapeutic approaches to inhibit aldosterone production. While MRAs are currently the treatment of choice for pathologic conditions due to aldosterone excess [6], they induce a counter-regulatory increase in aldosterone production [7] This may attenuate the effects of competitive MRAs, and might contribute to adverse cardiovascular effects through nongenomic mechanisms independent of activation of the mineralocorticoid receptor [8,9,10]. The therapeutic potential of targeting adrenal steroid synthesis to inhibit aldosterone production has not been fully explored due to the lack of selective aldosterone synthase inhibitors (ASIs)
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