Regulation of aldosterone secretion by Cav1.3.
Aldosterone-producing adenomas (APAs) vary in phenotype and genotype. Zona glomerulosa (ZG)-like APAs frequently have mutations of an L-type calcium channel (LTCC) CaV1.3. Using a novel antagonist of CaV1.3, compound 8, we investigated the role of CaV1.3 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, CaV1.2, over CaV1.3. In H295R cells transfected with wild-type or mutant CaV1.3 channels, the latter produced more aldosterone than wild-type, which was ameliorated by 100 μM of compound 8. In primary adrenal and non-transfected H295R cells, compound 8 decreased aldosterone production similar to high concentration of nifedipine (100 μM). Selective CaV1.3 blockade may offer a novel way of treating primary hyperaldosteronism, which avoids the vascular side effects of CaV1.2-blockade, and provides targeted treatment for ZG-like APAs with mutations of CaV1.3.
Clinical Pharmacology Unit, University of Cambridge, Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.
Catherine B
CB
Xie
Clinical Pharmacology Unit, University of Cambridge, Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.
Lalarukh Haris
LH
Shaikh
Clinical Pharmacology Unit, University of Cambridge, Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.
Sumedha
S
Garg
Clinical Pharmacology Unit, University of Cambridge, Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.
Gizem
G
Tanriver
Clinical Pharmacology Unit, University of Cambridge, Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.
Ada E D
AE
Teo
Clinical Pharmacology Unit, University of Cambridge, Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.
Junhua
J
Zhou
Clinical Pharmacology Unit, University of Cambridge, Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.
Carmela
C
Maniero
Human Research Tissue Bank, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
Wanfeng
W
Zhao
Department of Chemistry, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208-3113, USA.
Soosung
S
Kang
Department of Chemistry, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208-3113, USA.
Richard B
RB
Silverman
Clinical Pharmacology Unit, University of Cambridge, Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.|Department of Medicine, Faculty of Medicine, The National University of Malaysia (UKM) Medical Centre, Kuala Lumpur 56000, Malaysia.
Elena A B
EA
Azizan
Clinical Pharmacology Unit, University of Cambridge, Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.|Barts Heart Centre, William Harvey Research Institute, Queen Mary University London, London EC1M 6BQ, UK.
Morris J
MJ
Brown
D000450:Aldosterone / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D005838:Genotype; D006801:Humans; D009154:Mutation; D009543:Nifedipine / Q000494:pharmacology; D021381:Protein Transport
C472073:CACNA1D protein, human; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D000450:Aldosterone; D009543:Nifedipine