The Effects of Different Calcium Channel Blockers on Aldosterone-Producing Adenoma Cells.

Fen Wang,Xiaosen Ma,Anli Tong,Yuxiu Li,Yushi Zhang,Jin Wen

doi:10.3389/fendo.2020.00260

Abstract

Purpose: The aim of this study is to examine the effects of different kinds of calcium channel blockers (CCBs) on primary aldosterone-producing adenoma (APA) mainly with KCNJ5 mutations. Primary cultured APA cells were treated with different calcium channel blockers (L/T type CCB benidipine, T-type CCB mibefradil and L-type CCB nifedipine), and aldosterone secretagogues with or without nifedipine. Aldosterone level, aldosterone synthase (CYP11B2) mRNA expression and cell proliferation were detected. The results showed that all three CCBs significantly inhibit aldosterone secretion and CYP11B2 mRNA expression. Benidipine was relatively more effective than mibefradil or nifedipine. In addition, only mibefradil marginally inhibited cell proliferation. Adrenocorticotropin (ACTH) had a much stronger effect in stimulating aldosterone secretion and promoting cell proliferation from APA's than angiotensin II (ATII). Different from ACTH and ATII, potassium had no effect. Nifedipine inhibited the basal and ACTH-, ATII-elicited aldosterone secretion. Twenty three of 24 APAs had somatic KCNJ5 mutation. In conclusion, benidipine, mibefradil and nifedipine significantly inhibit aldosterone secretion in primary cultured APA cells.

Highlights

Primary aldosteronism is the most common secondary hypertension, accounting for about 10% of hypertension patients [1, 2], and is caused principally by aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia
The aim of the study was [1] to observe the effect of different kinds of calcium channel blockers (CCBs) especially benidipine on the aldosterone secretion and proliferation of primary cultured APA cells; [2] to investigate the effect of the three physiological stimuli (ACTH, angiotensin II (ATII) and potassium) on the aldosterone production and proliferation of APA cells, and the effects of stimuli combined with CCB on APA cells
We found that in APA cells, ACTH and ATII significantly stimulate aldosterone secretion, and ACTH was more effective than ATII, which is somewhat inconsistent with the fact that ATII is thought to be the major regulator in zona glomerulosa (ZAG) [17, 18]

Summary

Introduction

Primary aldosteronism is the most common secondary hypertension, accounting for about 10% of hypertension patients [1, 2], and is caused principally by aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia. The etiology has been identified in more than 50% of APA cases [3,4,5], involving several somatic gene mutations such as KCNJ5, ATP2B3, ATP1A1, and CACNA1D genes, with somatic KCNJ5 being the predominant mutation. A metaanalysis of 1636 APA patients revealed that the overall prevalence of somatic KCNJ5 mutations was 43%, ranging from 35% in Europe, the United States and Australia to 63% in Asia [3,4,5]. Germline mutations of KCNJ5, CACNA1D, and CACNA1H genes were found in patients with familial hyperaldosteronism [6, 7]. KCNJ5 gene codes G protein-activated inward rectifier potassium channel 4 (GIRK4). When KCNJ5 gene [9] and ATP1A1 [8] gene mutate, the increased intracellular Na+ concentration

Objectives

Methods

Results

Conclusion