MON-453 Clinical and Ex Vivo Comparisons of Aldosterone Suppression by Cinnarizine, a Putative Cav1.3 Inhibitor, With Nifedipine, a Non-selective Cav1.2/1.3 Inhibitor

Abstract E. Ng: None. A.E. Taylor: None. W.M. Drake: None. M.J. Brown: None. Introduction: 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 (CIN) fits the Cav1.3 crystal structure and has similar structure to Compound B, a Cav1.3 inhibitor which suppresses aldosterone ex vivo. Hypothesis Cav1.3 blockade by CIN may achieve similar, or greater, reduction in aldosterone secretion than non-selective Cav1.2/1.3 blockade by nifedipine (NIF). Methods Ex vivo Treatment of H295R cells with CIN at varying doses (technical and biological triplicates). Culture medium was collected to measure aldosterone levels; RNA extraction and qPCR were performed to evaluate CYP11B2 expression normalised to 18S as a housekeeping gene. Relative expression of CACNA1D and CACNA1C in H295R cells were measured by RNA sequencing (RNASeq). In vivo Prospective, open-label, Latin square crossover study of 15 adults with PA, with two weeks of either CIN 30 mg three times a day or NIF extended release 60 mg daily, separated by a two week washout. Interfering medications were ceased pre-study. The hierarchical primary outcome was change in aldosterone-to-renin ratio (ARR), urinary tetrahydroaldosterone (THA) and plasma aldosterone concentration (PAC) with CIN and NIF. Blood pressure (BP) change was a secondary outcome. The study had 90% power to detect 30% reduction in PAC. Parametric analysis was undertaken on log-transformed data. Results: Both NIF and CIN showed a dose-related reduction in aldosterone levels and CYP11B2 expression ex vivo. Mean change ± SEM in fold change of aldosterone levels and CYP11B2 relative to untreated were -0.47 ± 0.04 and -0.55 ± 0.06, respectively, with CIN 10-5 M and -0.52 ± 0.06 and -0.10 ± 0.10 with NIF 10-4 M. RNASeq reads were 5.99 (0.15) (mean(SD)) for CACNA1C and 16.29 (0.47) for CACNA1D. Of the 15 subjects in the crossover trial, 13 were male, 10 Black, age 55 ± 13. NIF reduced ARR (median (IQR) 2650 (1163-4043) to 1808 (825-2946) pmol/L:nmol/L/h) but not CIN (2458 (1268-3764) to 2739 (1795-3751) pmol/L:nmol/L/h) (f=5.15, p=0.040, repeated measures ANOVA). Similar trends were seen for urinary THA (f=5.04, p=0.043) but not PAC. BP fell by 18±13 / 8±10 mmHg with NIF and 6±14 / 5±10 mmHg with CIN (p<0.01 for BP fall on NIF). Conclusion: CIN was less effective than NIF in inhibiting aldosterone production by H295R cells, despite an estimated excess of CACNA1D (encoding Cav1.3) over CACNA1C (Cav1.2). Similarly in the patients, NIF was more effective at lowering ARR. The efficacy of CIN is probably limited by solubility ex vivo, and dose in vivo, and by its mixed pharmacology including dopamine blockade. The potential for a more effective and specific Cav1.3 blocker in PA is illustrated by the <50% reduction in ARR on NIF, likely due to direct adrenal inhibition (Cav1.3) being offset by baroreceptor stimulation of renin-aldosterone. Monday, June 3, 2024