Aim: Inhibitors of dopamine-β-hydroxylase (DβH), such as zamicastat,
emerged as promising drugs for pulmonary arterial hypertension (PAH).
This study intended to validate the mechanism of action of zamicastat by
studying its effect on the overdrive of sympathetic nervous system
(SNS). Methods: This was a single-centre, prospective, double-blind,
randomised, placebo-controlled, crossover study, with 400 mg zamicastat,
in 22 healthy male subjects. Cold pressor test (CPT) was performed at
screening and each treatment period at day 1 and day 10. The
concentration of dopamine (DA), epinephrine (EPI), norepinephrine (NE)
in plasma and 24h-urine, and DβH activity in plasma were measured.
Results: For zamicastat compared to placebo, the difference between cold
stimulus and rest phases on the change from baseline to day 10 of CPT
showed an estimated decrease of -4.62 mmHg for systolic blood pressure
(SBP; p=0.020). Zamicastat caused a decrease of -2.62 mmHg in mean
arterial pressure (MAP) response to cold stimulus during CPT (p=0.025).
At day 10, zamicastat elicited a statistically significant increase of
12.63 ng/L (p=0.040) and 19.22 ng/L (p=0.001) in plasma DA, before CPT
and after CPT, and a significant estimated increase in plasma EPI change
from baseline after CPT (p=0.040). Inhibition of plasma DβH activity
ranged from 19.8% to 25.0%. At day 10, statistically significant
reductions in 24-hour urinary excretion of EPI (p=0.002) and NE
(p=0.001) were observed. Conclusions: Zamicastat decreased SBP and MAP
response to cold stimulus during CPT, evidencing its effect on the
overdrive sympathetic response to cold stimulus.