AimsDopamine 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).MethodsA 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.ResultsCompared 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.ConclusionsOur results demonstrated the effect of zamicastat on the overdrive sympathetic response to cold stimulus, confirming its potential as SNS modulator.

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扎米卡司他对冷加压试验的血压和心率反应的影响：健康受试者的双盲、随机、安慰剂对照研究


目的多巴胺 β-羟化酶 (DβH) 抑制剂，如扎米卡司他，有望治疗肺动脉高压。本研究旨在通过研究扎米卡司他对交感神经系统（SNS）过度驱动的影响来验证扎米卡司他的作用机制。方法一项单中心、前瞻性、双盲、随机、安慰剂对照、交叉研究评估了扎米卡司他的作用。 22 名健康男性受试者服用 400 毫克扎米司他。在筛选时以及第-1天和第10天的每个治疗期进行冷加压试验（CPT）。血浆和24小时尿液中多巴胺（DA）、肾上腺素（EPI）和去甲肾上腺素（NE）的水平以及血浆DβH活性测量结果与安慰剂相比，扎米卡司他在冷刺激期间收缩压降低了 − 4.62 mmHg与。 CPT 第 10 天的休息阶段（磷=.020）。扎米卡司他降低了 CPT 期间对冷刺激的平均动脉压反应（−2.62 mmHg；磷= .025)。第 10 天，CPT 前，扎米卡司他显着增加血浆 DA（12.63 ng/L；磷= .040) 和 CPT 后 (19.22 ng/L；磷= .001) 以及 CPT 后估计的血浆 EPI 相对于基线的变化 (磷= .040)。血浆DβH活性的抑制范围为19.8%至25.0%。第 10 天，EPI 24 小时尿排泄量显着减少（磷= .002) 和 NE (磷= .001) 被观察到。扎米卡司他C τ几何平均值±GSD范围为第3天的45.86±1.46ng/mL到第10天的58.64±1.52ng/mL，具有中等的个体间变异性（CV：32.6%–36.6%）。第 6 天就已经达到稳定状态。结论我们的结果证明了扎米卡司他对寒冷刺激的过度交感神经反应的影响，证实了其作为 SNS 调节剂的潜力。