title: The angiotensin II type 1 receptor-neprilysin inhibitor LCZ696 blocked aldosterone synthesis in a human adrenocortical cell line.
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/AT1receptor-induced aldosterone (Ald) synthesis in human adrenocortical cells. The binding affinity of valsartan+LBQ657 (active moiety of sacubitril) to the AT1receptor was greater than that of valsartan alone in an AT1receptor-expressing human embryonic kidney cell-based assay. There was no difference in the dissociation from the AT1receptor 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 AT1receptor, 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/AT1receptor-induced Ald synthesis in human adrenocortical cells.
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.|Department of Molecular Cardiovascular Therapeutics, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Shin-Ichiro
authors.initials: SI
authors.lastname: Miura
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Suematsu
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Yoshino
authors.initials: Y
authors.lastname: Matsuo
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Sayo
authors.initials: S
authors.lastname: Tomita
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Nakayama
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Goto
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Arimura
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuwano
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Yahiro
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.|Department of Molecular Cardiovascular Therapeutics, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Keijiro
authors.initials: K
authors.lastname: Saku
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000450:Aldosterone / Q000096:biosynthesis*; D000613:Aminobutyrates / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002460:Cell Line; D004338:Drug Combinations; D006801:Humans; D015260:Neprilysin / Q000037:antagonists & inhibitors; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D000068756:Valsartan / Q000494:pharmacology
chemical_list: D000613:Aminobutyrates; D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000450:Aldosterone; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination