Key result
In a human adrenocortical cell line, ARBs differentially inhibited Ang II-induced aldosterone synthesis, and the addition of ANP provided an additive inhibitory effect.
The addition of ANP to ARB therapy may provide additive inhibition of aldosterone synthesis, supporting the mechanistic rationale for dual AT1 receptor and neprilysin inhibition.
No immediate practice change; hypothesis-generating for additive aldosterone suppression via ARB plus ANP or dual AT1/neprilysin inhibition.
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(-8 )M. 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(-7 )M) without ARBs inhibited Ald synthesis, and the combination of ANP (10(-7 )M) and ARB (10(-8 )M) 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.
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Miura et al. (2014) studied Aldosterone synthesis. ARBs with or without ANP vs. Ang II alone / ARBs alone was evaluated on Ang II-induced adrenal aldosterone synthesis. In a human adrenocortical cell line, ARBs differentially inhibited Ang II-induced aldosterone synthesis, and the addition of ANP provided an additive inhibitory effect.
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