Effect of zamicastat on blood pressure and heart rate response to cold pressor test: A double‐blind, randomized, placebo‐controlled study in healthy subjects

• Published in: British journal of clinical pharmacology Vol. 90; no. 11; pp. 2781 - 2792
• Main Authors: Fonseca, Marlene, Ribeiro, Cheila, Castilla‐Fernández, Guillermo, Gama, Helena, Magalhães, Luís, Henriques, Sara Carolina, Silva, Nuno, Pinto, Filipe, Almeida, Luís, Soares‐da‐Silva, Patrício
• Format: Journal Article
• Language: English
• Published: England 01.11.2024
• Subjects: Adult; blood pressure; Blood Pressure - drug effects; catecholamines; cold pressor test; Cold Temperature; Cross-Over Studies; Dopamine; Dopamine beta-Hydroxylase - antagonists & inhibitors; Double-Blind Method; Epinephrine - blood; Healthy Volunteers; heart rate; Heart Rate - drug effects; Humans; Male; Norepinephrine - blood; Prospective Studies; Sympathetic Nervous System - drug effects; Young Adult; zamicastat; cold pressor test; blood pressure; catecholamines; heart rate; zamicastat
• DOI: 10.1111/bcp.16167
• ISSN: 0306-5251; 1365-2125

Aims Dopamine beta‐hydroxylase (DβH) inhibitors, like zamicastat, hold promise for treating pulmonary arterial hypertension. This study aimed to validate the mechanism of action of zamicastat by studying its effect on the overdrive of the sympathetic nervous system (SNS). Methods A single‐centre, prospective, double‐blind, randomized, placebo‐controlled, crossover study evaluated the effect of 400 mg zamicastat in 22 healthy male subjects. Cold pressor test (CPT) was performed at screening and each treatment period on Days −1 and 10. Plasma and 24 h‐urine levels of dopamine (DA), epinephrine (EPI) and norepinephrine (NE), and plasma DβH activity, were measured. Results Compared to placebo, zamicastat showed a − 4.62 mmHg decrease in systolic blood pressure during the cold stimulus vs. rest phases on Day 10 of CPT (P = .020). Zamicastat decreased mean arterial pressure response to cold stimulus during CPT (−2.62 mmHg; P = .025). At Day 10, zamicastat significantly increased plasma DA, before CPT (12.63 ng/L; P = .040) and after CPT (19.22 ng/L; P = .001) as well as the estimated plasma EPI change from baseline after CPT (P = .040). Inhibition of plasma DβH activity ranged from 19.8% to 25.0%. At Day 10, significant reductions in 24‐h urinary excretion of EPI (P = .002) and NE (P = .001) were observed. Zamicastat Cτ geometric mean ± GSD ranged from 45.86 ± 1.46 ng/mL on Day 3 to 58.64 ± 1.52 ng/mL on Day 10, with moderate inter‐individual variability (CV: 32.6%–36.6%). Steady state was already achieved on Day 6. Conclusions Our results demonstrated the effect of zamicastat on the overdrive sympathetic response to cold stimulus, confirming its potential as SNS modulator.