Abstract
CONTEXT: Primary aldosteronism (PA) is commonly caused by somatic mutations of CACNA1D encoding Cav1.3, one of the four L-type calcium channels. The over-the-counter drug, cinnarizine, fits the Cav1.3 crystal structure pore domain. OBJECTIVE: We hypothesized that Cav1.3 blockade by cinnarizine may achieve similar, or greater, reduction in aldosterone secretion than nonselective Cav1.2/1.3 blockade by nifedipine. METHODS: Separate wells of angiotensin II-stimulated HAC15 cells were treated with either cinnarizine (1-30 μM) or nifedipine (1-100 μM). Aldosterone concentrations were measured in culture medium; RNA extraction and quantitative polymerase chain reaction were performed to evaluate CYP11B2 expression. A prospective, open-label, crossover study was conducted of 15 adults with PA, treated with 2 weeks of cinnarizine 30 mg 3 times a day or nifedipine extended release 60 mg daily, separated by a 2-week washout. The hierarchical primary outcome was change in aldosterone-to-renin ratio (ARR), urinary tetrahydroaldosterone (THA), and plasma aldosterone concentration (PAC). Blood pressure change was a secondary outcome. Parametric analysis was undertaken on log-transformed data. (ClinicalTrials.gov: NCT05686993). RESULTS: Both drugs reduced aldosterone concentrations and CYP11B2 expression in vitro. Mean changes ± SEM in fold change of aldosterone concentrations and CYP11B2 were -0.47 ± 0.05 and -0.56 ± 0.07, respectively, with cinnarizine 30 μM and -0.59 ± 0.05 and -0.78 ± 0.07 with nifedipine 100 μM. In the clinical crossover trial, ARR was reduced by nifedipine but not cinnarizine (F = 3.25; P = .047); PAC rose with both drugs (F = 4.77; P = .013), but urinary THA was unchanged. CONCLUSION: A Cav1.3 ligand, cinnarizine, reduced aldosterone secretion from adrenocortical cells, but at maximum-soluble concentrations was less effective than the nonselective calcium blocker, nifedipine. At clinical doses, cinnarizine did not reduce plasma ARR in patients with PA, and, as in vitro, was inferior to nifedipine. The limited efficacy of high-dose nifedipine may be due to incomplete Cav1.3 blockade, or to a role for non-L-type calcium channels in aldosterone secretion.