Novel molecular mechanisms in the inhibition of adrenal aldosterone synthesis: Action of tolvaptan via vasopressin V2 receptor-independent pathway.

British Journal of Pharmacology
Yusuf AliMasaaki Ito

Abstract

We investigated the inhibitory effect and associated molecular mechanisms of tolvaptan on angiotensin II (AngII)-induced aldosterone production in vitro and in vivo. In vitro, H295R human adrenocarcinoma cells were incubated with 1 μmol·L-1 arginine vasopressin (AVP) or dDAVP, or tolvaptan (0.1, 1, and 3 μmol·L-1 ) in the presence and absence of 100 nmol·L-1 of AngII. In vivo, Sprague-Dawley rats were treated with tolvaptan 0.05% in the diet for 6 days in the presence and absence of 200 pmol·min-1 AngII. Tolvaptan suppressed AngII-induced aldosterone production in a dose-dependent manner in H295R cells, whereas neither AVP nor dDAVP in the presence or absence of AngII altered aldosterone production, suggesting the vasopressin V2 receptor was not involved in the inhibitory effect of tolvaptan on aldosterone synthesis. In addition, tolvaptan inhibited the AngII-induced increase in aldosterone synthase (CYP11B2) protein levels without suppressing CYP11B2 mRNA expression. Notably, tolvaptan increased the levels of unfolded protein response (UPR) marker DDIT3 and eIF2α phosphorylation (a UPR-induced event), which could block the translation of CYP11B2 mRNA into protein and thereby inhibit aldosterone production. In vivo, tolvaptan s...Continue Reading

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Citations

May 1, 2021·International Journal of Molecular Sciences·Yoshimichi TakedaYoshiyu Takeda

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