The discovery of primary aldosteronism (PA) genotypes and correlating phenotypes calls for targeted and personalised therapy. PA caused by CACNA1D mutations may benefit from Cav1.3 inhibition. Cinnarizine fits the Cav1.3 crystal structure pore domain. We hypothesised that Cav1.3 blockade by cinnarizine may achieve similar, or greater, reduction in aldosterone secretion than non-selective Cav1.2/1.3 blockade by nifedipine.
For in vitro studies, HAC15 cells were treated with cinnarizine (1-30 uM) and nifedipine (1-100 uM) with angiotensin-II stimulation. Aldosterone concentrations were measured in culture medium; RNA extraction and qPCR were performed to evaluate CYP11B2 expression.
We then conducted a prospective, open-label, crossover study of 15 adults with PA, treated with two weeks of cinnarizine 30mg three times a day or nifedipine extended-release 60mg daily, separated by a two week washout. The hierarchical primary outcome was change in aldosterone-to-renin ratio (ARR), urinary tetrahydroaldosterone (THA) and plasma aldosterone concentration (PAC). Blood pressure (BP) change was a secondary outcome. Parametric analysis was undertaken on log-transformed data. (ClinicalTrials.gov: NCT05686993)
Both drugs showed a dose-related reduction in aldosterone concentrations and CYP11B2 expression in vitro. Mean change ± SEM in fold change of aldosterone concentrations and CYP11B2 relative to angiotensin-II alone were -0.43±0.06 and -0.59±0.14, respectively, with cinnarizine 30uM and -0.59 ± 0.03 and -0.78 ± 0.18 with nifedipine 100uM. In the crossover trial, nifedipine reduced ARR but not cinnarizine (F=3.25, p=0.047), both increased PAC (F=4.77, p=0.013) (repeated measures ANOVA) but did not change urinary THA.
Nifedipine was more effective than cinnarizine in inhibiting aldosterone production in vitro and lowering ARR in vivo.