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Study of aldosterone synthase inhibition as an add-on therapy in resistant hypertension.

ABSTRACT: Aldosterone inhibition with mineralcorticoid receptor antagonists (MRAs) is an effective treatment for resistant hypertension. Aldosterone synthase inhibitors (ASIs) are currently being investigated as a new therapeutic strategy to reduce aldosterone secretion from the adrenal gland. In this study, the efficacy and safety of the first-generation ASI LCI699 (0.25 mg twice daily, 1 mg 4 once daily, and 0.5 mg/1 mg twice daily) was compared with placebo and eplerenone (50 mg twice daily), in patients with resistant hypertension. Placebo-adjusted decreases in systolic blood pressure (BP) with LCI699 ranged from 2.6 mm Hg to 4.3 mm Hg at week 8; changes in diastolic BP ranged from +0.3 mm Hg to -1.2 mm Hg. However, reductions were smaller than observed with eplerenone 50 mg twice daily (9.9 mm Hg and 2.9 mm Hg for systolic and diastolic BP, respectively) and not statistically significant vs placebo. LCI699 suppressed plasma aldosterone levels in a dose-related manner with corresponding dose-dependent increases in plasma renin activity and plasma 11-deoxycorticosterone. LCI699 and eplerenone were well tolerated. These data demonstrate that aldosterone synthesis inhibition with LCI699 lowers BP modestly in patients with resistant hypertension. Aldosterone synthesis inhibition might offer an attractive adjunct to aldosterone receptor blockade, although the potential of a combination MRA/ASI has not yet been tested.

SUBMITTER: Karns AD

PROVIDER: S-EPMC8033888 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aldosterone is a major mineralocorticoid hormone that plays a key role in the regulation of electrolyte balance and blood pressure. Excess aldosterone levels can arise from dysregulation of the renin-angiotensin-aldosterone system and are implicated in the pathogenesis of hypertension and heart failure. Aldosterone synthase (cytochrome P450 11B2, CYP11B2) is the sole enzyme responsible for the production of aldosterone in humans. Blocking of aldosterone synthesis by mediating aldosterone synthase activity is thus a recently emerging pharmacological therapy for hypertension, yet a lack of structural information has limited this approach. Here, we present the crystal structures of human aldosterone synthase in complex with a substrate deoxycorticosterone and an inhibitor fadrozole. The structures reveal a hydrophobic cavity with specific features associated with corticosteroid recognition. The substrate binding mode, along with biochemical data, explains the high 11?-hydroxylase activity of aldosterone synthase toward both gluco- and mineralocorticoid formation. The low processivity of aldosterone synthase with a high extent of intermediates release might be one of the mechanisms of controlled aldosterone production from deoxycorticosterone. Although the active site pocket is lined by identical residues between CYP11B isoforms, most of the divergent residues that confer additional 18-oxidase activity of aldosterone synthase are located in the I-helix (vicinity of the O(2) activation path) and loops around the H-helix (affecting an egress channel closure required for retaining intermediates in the active site). This intrinsic flexibility is also reflected in isoform-selective inhibitor binding. Fadrozole binds to aldosterone synthase in the R-configuration, using part of the active site cavity pointing toward the egress channel. The structural organization of aldosterone synthase provides critical insights into the molecular mechanism of catalysis and enables rational design of more specific antihypertensive agents.

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Study of aldosterone synthase inhibition as an add-on therapy in resistant hypertension.

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