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 (AT) 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/AT receptor-induced aldosterone (Ald) synthesis in human adrenocortical cells. The binding affinity of valsartan+LBQ657 (active moiety of sacubitril) to the AT receptor was greater than that of valsartan alone in an AT receptor-expressing human embryonic kidney cell-based assay. There was no difference in the dissociation from the AT 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 AT 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/AT receptor-induced Ald synthesis in human adrenocortical cells.

Pharmacodynamic and Pharmacokinetic Profiles of Sacubitril/Valsartan (LCZ696) in Patients with Heart Failure and Reduced Ejection Fraction

“…As both NPs and RAAS blockers may decrease aldosterone levels, it is not clear to what extent these findings reflect AT 1 ‐receptor blockade or NP facilitation, or both combined. Of note, a recent preclinical report showed that combined neprilysin and AT 1 blockade enhanced the aldosterone suppression effects of ANP and BNP in Ang‐II‐sensitized human adrenocortical cells . Similarly, combined neprilysin and AT 1 blockade more effectively attenuated Ang‐II mediated hypertrophic and fibrotic effects on cardiac and renal cells compared with stand‐alone neprilysin inhibition and AT 1 blockade .…”

Dual inhibitory action on aldosterone by combined angiotensin receptor antagonism and neprilysin inhibition

“…17 The authors also showed that the natriuretic peptide-mediated suppression of aldosterone synthesis was further augmented by co-administration of LBQ657. 17 Collectively, the authors demonstrated that the combined AT1R antagonism by valsartan and LBQ657 neprilysin inhibition significantly enhanced the natriuretic peptide-mediated signaling effects to suppress Ang II-AT1R-induced aldosterone production in adrenocortical cells, without affecting the expression of aldosterone synthase genes 17 (Figure 1). The results revealed a dual inhibitory action of LCZ696 on the aldosterone cascade as an important drug property and revealed a new aspect of the mechanism of LCZ696-mediated beneficial effects in cardiovascular and renal physiology, thereby contributing an interesting finding to the field of hypertension research.…”

“…Indeed, in one study, LCZ696 treatment significantly increased the circulating ANP and cGMP concentrations, but did not affect plasma aldosterone concentration compared with placebo in hypertensive patients. 11 Interestingly, Miura et al, 17 as reported in this issue, examined the effects of valsartan, ARB and LBQ657-the active moiety of LCZ696-on aldosterone synthesis in a human adrenocortical cell line (NCI-H295R cells) to investigate the possible mechanisms of the beneficial effects of LCZ696. 17 Although there was no difference in the dissociation from AT1R between valsartan +LBQ657 and valsartan alone, the binding affinity of valsartan+LBQ657 to AT1R was greater than that of valsartan alone in an AT1R-expressing human embryonic kidney cell-based living assay.…”

“…11 Interestingly, Miura et al, 17 as reported in this issue, examined the effects of valsartan, ARB and LBQ657-the active moiety of LCZ696-on aldosterone synthesis in a human adrenocortical cell line (NCI-H295R cells) to investigate the possible mechanisms of the beneficial effects of LCZ696. 17 Although there was no difference in the dissociation from AT1R between valsartan +LBQ657 and valsartan alone, the binding affinity of valsartan+LBQ657 to AT1R was greater than that of valsartan alone in an AT1R-expressing human embryonic kidney cell-based living assay. 17 The authors also showed that the natriuretic peptide-mediated suppression of aldosterone synthesis was further augmented by co-administration of LBQ657.…”

“…17 Although there was no difference in the dissociation from AT1R between valsartan +LBQ657 and valsartan alone, the binding affinity of valsartan+LBQ657 to AT1R was greater than that of valsartan alone in an AT1R-expressing human embryonic kidney cell-based living assay. 17 The authors also showed that the natriuretic peptide-mediated suppression of aldosterone synthesis was further augmented by co-administration of LBQ657. 17 Collectively, the authors demonstrated that the combined AT1R antagonism by valsartan and LBQ657 neprilysin inhibition significantly enhanced the natriuretic peptide-mediated signaling effects to suppress Ang II-AT1R-induced aldosterone production in adrenocortical cells, without affecting the expression of aldosterone synthase genes 17 (Figure 1).…”