Regulation of aldosterone secretion by Ca(v)1.3

Aldosterone-producing adenomas (APAs) vary in phenotype and genotype. Zona glomerulosa (ZG)-like APAs frequently have mutations of an L-type calcium channel (LTCC) 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 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 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.