Comparison of aldosterone synthesis in adrenal cells, effect of various AT₁ receptor blockers with or without atrial natriuretic peptide

Abstract

Bifunctional angiotensin II (Ang II) type 1 (AT₁) receptor blockers (ARBs) that can block the activation of not only AT₁ receptor, but also neprilysin, which metabolizes vasoactive peptides including atrial natriuretic peptide (ANP), are currently being developed. However, the usefulness of the inactivation of ANP in addition to the AT₁ receptor with regard to aldosterone (Ald) synthesis is not yet clear. We evaluated the inhibitory effects of various ARBs combined with or without ANP on Ang II-induced adrenal Ald synthesis using a human adrenocortical cell line (NCI-H295R). Ang II increased Ald synthesis in a dose- and time-dependent manner. Ald synthesis induced by Ang II was completely blocked by azilsartan, but not PD123319 (AT₂ receptor antagonist). CGP42112 AT₂ receptor agonist did not affect Ald synthesis. While most ARBs block Ang II-induced Ald synthesis to different extents, azilsartan and olmesartan have similar blocking effects on Ald synthesis. The different effects of ARBs were particularly observed at 10⁻⁷ and 10⁻⁸M. ANP attenuated Ang II-induced Ald synthesis, and ANP-mediated attenuation of Ang II-induced Ald synthesis were blocked by inhibitors of G-protein signaling subtype 4 and protein kinase G. ANP (10⁻⁸ and 10⁻⁷M) without ARBs inhibited Ald synthesis, and the combination of ANP (10⁻⁷M) and ARB (10⁻⁸M) had an additive effect with respect to the inhibition of Ald synthesis. In conclusions, ARBs had differential effects on Ang II-induced Ald synthesis, and ANP may help to block Ald synthesis when the dose of ARB is not sufficient to block its secretion.

• Adrenocortical cell
• aldosterone
• atrial natriuretic peptide
• bifunctional angiotensin II type 1 receptor blocker
• molecule-specific effects

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Declaration of interest

KS and SM have received grants and lecture honoraria from Daiichi-Sankyo Co. Ltd., MSD, Dainippon Sumitomo Pharma Co. Ltd., Takeda Pharma Co. Ltd., Boehringer Ingelheim and Astellas Pharma Inc. KS is a Chief Director and SM is a Director of NPO Clinical and Applied Science, Fukuoka, Japan. KS has an Endowed Department of “Department of Molecular Cardiovascular Therapeutics” supported by MSD, Co. Ltd. SM belongs to the Department of Molecular Cardiovascular Therapeutics supported by MSD, Co. Ltd.