Department of Research, BIAL - Portela & Cª, S.A., Coronado (S. Romão e S. Mamede), Portugal.
Department of Research, BIAL - Portela & Cª, S.A., Coronado (S. Romão e S. Mamede), Portugal; Department of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Portugal.
Eur J Pharmacol. 2019 Jan 5;842:125-132. doi: 10.1016/j.ejphar.2018.10.030. Epub 2018 Oct 26.
Hyperactivity of sympathetic nervous system plays an important role in the development and progression of cardiovascular diseases. An approach to mitigate the enhanced sympathetic nervous system drive is restricting the biosynthesis of noradrenaline via inhibition of the enzyme dopamine β-hydroxylase (DβH), that catalyzes the hydroxylation of dopamine to noradrenaline in sympathetic nerves. The aim of the present study was to evaluate the effects of zamicastat, a novel DβH inhibitor that decreases noradrenaline and increases dopamine levels in peripheral sympathetically innervated tissues, on the hemodynamic and cardiometabolic parameters in salt-induced hypertension and heart failure in the Dahl salt-sensitive (SS) rat. Zamicastat (10, 30 and 100 mg/kg body weight) was tested acutely against salt-induced hypertension in the Dahl SS rat. Chronic zamicastat treatment (30 mg/kg/day) was evaluated against salt-induced cardiac hypertrophy and biomarkers of cardiometabolic risk and inflammation in Dahl SS rats and upon the survival rate in aged Dahl SS rats fed a high-salt diet. The reduction in the sympathetic tone attained with zamicastat shaped a dose- and time-dependent effect on blood pressure. Prolonged treatment with zamicastat ameliorated end-organ damage, metabolic syndrome and inflammation hallmarks in hypertensive Dahl SS rats. Survival rate of Dahl SS rats fed a high-salt diet demonstrated that zamicastat increased median survival of Dahl SS rats fed a high-salt diet. The use of DβH inhibitors, like zamicastat, is a promising approach to treat hypertension, heart failure and cardiovascular diseases where a reduction in the sympathetic tone has beneficial effects.
交感神经系统的过度活跃在心血管疾病的发展和进展中起着重要作用。减轻增强的交感神经系统驱动的一种方法是通过抑制多巴胺β-羟化酶（DβH）来限制去甲肾上腺素的生物合成，该酶催化多巴胺在交感神经中的羟化生成去甲肾上腺素。本研究的目的是评估 zamicastat（一种新型的 DβH 抑制剂，可降低外周交感神经支配组织中的去甲肾上腺素并增加多巴胺水平）对盐诱导的高血压和心力衰竭中 Dahl 盐敏感（SS）大鼠的血流动力学和心脏代谢参数的影响。急性给予 zamicastat 测试其对 Dahl SS 大鼠盐诱导性高血压的作用。慢性 zamicastat 治疗（30mg/kg/天）评估了其对盐诱导的 Dahl SS 大鼠心脏肥大和心脏代谢风险及炎症生物标志物的作用以及在高盐饮食喂养的老年 Dahl SS 大鼠中的存活率。Zamicastat 降低交感神经张力的作用呈剂量和时间依赖性，对血压产生影响。长期用 zamicastat 治疗可改善高血压 Dahl SS 大鼠的靶器官损伤、代谢综合征和炎症特征。高盐饮食喂养的 Dahl SS 大鼠的存活率表明，zamicastat 增加了高盐饮食喂养的 Dahl SS 大鼠的中位存活率。使用 DβH 抑制剂（如 zamicastat）是治疗高血压、心力衰竭和心血管疾病的一种有前途的方法，这些疾病中降低交感神经张力具有有益作用。
