The Angiotensin II Type 1 Receptor-Neprilysin Inhibitor LCZ696 Blocked Aldosterone Synthesis in a Human Adrenocortical Cell Line

Shin-Ichiro Miura, Yasunori Suematsu, Yoshino Matsuo, Sayo Tomita, Asuka Nakayama, Masaki Goto, Tadaaki Arimura, Takashi Kuwano, Eiji Yahiro, Keijiro Saku

Hypertens Res. 2016 Nov;39(11):758-763.

PMID: 27334058

Abstract:

A recent clinical study indicated that an angiotensin II (Ang II) type 1 (AT1) receptor-neprilysin inhibitor (ARNi) designated LCZ696 (sacubitril/valsartan, as combined sodium complex) was superior to enalapril at reducing the risks of death and hospitalization due to heart failure. Therefore, we investigated the possible mechanisms of the beneficial effect of LCZ696, in which the inhibition of neprilysin enhances atrial natriuretic peptide (NP) or brain NP (ANP or BNP)-evoked signals that can block Ang II/AT1 receptor-induced aldosterone (Ald) synthesis in human adrenocortical cells. The binding affinity of valsartan+LBQ657 (active moiety of sacubitril) to the AT1 receptor was greater than that of valsartan alone in an AT1 receptor-expressing human embryonic kidney cell-based assay. There was no difference in the dissociation from the AT1 receptor between valsartan+LBQ657 and valsartan alone. In Ang II-sensitized human adrenocortical cells, ANP or BNP alone, but not LBQ657 or valsartan alone, significantly decreased Ald synthesis. The level of suppression of Ald synthesis by ANP or BNP with LBQ657 was greater than that by ANP or BNP without LBQ657. The suppression of ANP was blocked by inhibitors of regulator of G-protein signaling proteins and cyclic GMP-dependent protein kinase. The inhibition of neprilysin did not change the mRNA levels of the AT1 receptor, ANP receptor A, regulator of G-protein signaling protein, renin or 3β-hydroxysteroid dehydrogenases. In conclusion, the inhibition of neprilysin by LBQ657 enhances the NP-evoked signals that can block Ang II/AT1 receptor-induced Ald synthesis in human adrenocortical cells.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP149709444	LBQ657		149709-44-4	Price

Catalog Number

Product Name

Structure

CAS Number

Price

AP149709444

LBQ657

149709-44-4

Price

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