Regulation of aldosterone secretion by Ca v 1.3

Catherine B. Xie, Lalarukh Haris Shaikh, Sumedha Garg, Gizem Tanriver, Ada E.D. Teo, Junhua Zhou, Carmela Maniero, Wanfeng Zhao, Soosung Kang, Richard B. Silverman, Elena A.B. Azizan, Morris J. Brown

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32 Scopus citations

Abstract

Aldosterone-producing adenomas (APAs) vary in phenotype and genotype. Zona glomerulosa (ZG)-like APAs frequently have mutations of an L-type calcium channel (LTCC) Ca V 1.3. Using a novel antagonist of Ca V 1.3, compound 8, we investigated the role of Ca V 1.3 on steroidogenesis in the human adrenocortical cell line, H295R, and in primary human adrenal cells. This investigational drug was compared with the common antihypertensive drug nifedipine, which has 4.5-fold selectivity for the vascular LTCC, Ca V 1.2, over Ca V 1.3. In H295R cells transfected with wild-type or mutant Ca V 1.3 channels, the latter produced more aldosterone than wild-type, which was ameliorated by 100 1/4M of compound 8. In primary adrenal and non-transfected H295R cells, compound 8 decreased aldosterone production similar to high concentration of nifedipine (100 1/4M). Selective Ca V 1.3 blockade may offer a novel way of treating primary hyperaldosteronism, which avoids the vascular side effects of Ca V 1.2-blockade, and provides targeted treatment for ZG-like APAs with mutations of Ca V 1.3.

Original languageEnglish
Article number24697
JournalScientific Reports
Volume6
DOIs
StatePublished - 21 Apr 2016

Bibliographical note

Funding Information:
This work is supported by NIHR Senior Investigator grant NF-SI-051210052 awarded to M.J.B.; the Austin Doyle Award (Servier Australia) and the Tunku Abdul Rahman Centenary Fund (St Catharines College, Cambridge, UK) awarded to E.A.B.A.; Gates Cambridge Scholarship awarded to C.B.X.; L.H.S., S.G. and C.M. are supported by the British Heart Foundation PhD studentship FS/11/35/28871, FS/14/75/31134 and FS/14/12/30540 respectively; J.Z. was supported by the Cambridge Overseas Trust Scholarship and the Sun Hung Kai Properties-Kwoks Foundation; A.E.D.T. is funded by the Agency for Science, Technology & Research (A∗STAR) Singapore and Wellcome Trust Award 085686/Z/08/A; LHS, JZ and EABA were further supported by the NIHR Cambridge Biomedical Research Centre; the Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. The CaV1.3 constructs were kindly gifted by Dr. Joerg Striessnig and Dr Petronel Tuluc.

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