Igreja Bruno, Pires Nuno, Loureiro Ana, Wright Lyndon, Soares-da-Silva Patrício
Department of Research, BIAL - Portela & Ca, S.A., Coronado (S. Mamede e S. Romão) 4747-457, Portugal.
Department of Biomedicine, Unit of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto, Porto 4200-319, Portugal.
ACS Pharmacol Transl Sci. 2019 Sep 4;2(5):353-360. doi: 10.1021/acsptsci.9b00039. eCollection 2019 Oct 11.
The hyperactivity of the sympathetic nervous system (SNS) plays a major role in the development and progression of several cardiovascular diseases. One strategy to mitigate the SNS overdrive is by restricting the biosynthesis of norepinephrine via the inhibition of dopamine β-hydroxylase (DBH). Zamicastat is a new DBH inhibitor that decreases norepinephrine and increases dopamine levels in peripherally sympathetic-innervated tissues. The cardiometabolic and inflammatory effects of sympathetic down-regulation were evaluated in 50 week old male spontaneously hypertensive rats (SHRs) receiving zamicastat (30 mg/kg/day) for 9 weeks. After 8 weeks of treatment, the blood pressure (BP) and heart rate (HR) were assessed by tail cuff plethysmography. At the end of the study, 24 h urine, plasma, heart, and kidney were collected for biochemical and morphometric analyses. Zamicastat-induced sympathetic down-regulation decreased the high BP in SHRs, with no observed effect on HR. The heart-to-body weight ratio was lower in SHRs treated with zamicastat, whereas the body weight and kidney-to-body weight ratio were similar between both SHR cohorts. Zamicastat-treated SHRs showed reduced 24 h urine output, but the urinary amount of protein excreted and creatinine clearance rate remained unchanged. Zamicastat treatment significantly decreased plasma triglycerides, free fatty acids, and aspartate aminotransferase levels. Aged SHRs showed higher plasma levels of inflammatory markers as compared with age-matched normotensive Wistar-Kyoto rats. The inflammatory benefits attained with DBH inhibition were expressed by a decrease in CRP, MCP-1, IL-5, IL-17α, GRO/KC, MIP-1α, and RANTES plasma levels as compared with untreated SHRs. In conclusion, DBH inhibition decreased norepinephrine levels, reduced end-organ damage, and improved cardiometabolic and inflammatory biomarkers in aged male SHRs.
交感神经系统（SNS）的功能亢进在多种心血管疾病的发生和发展中起主要作用。减轻SNS过度兴奋的一种策略是通过抑制多巴胺β-羟化酶（DBH）来限制去甲肾上腺素的生物合成。扎米卡司他是一种新型DBH抑制剂，可降低去甲肾上腺素水平，并提高外周交感神经支配组织中的多巴胺水平。对50周龄雄性自发性高血压大鼠（SHRs）给予扎米卡司他（30mg/kg/天）9周，以评估交感神经下调对心脏代谢和炎症的影响。治疗8周后，通过尾袖体积描记法评估血压（BP）和心率（HR）。在研究结束时，收集24小时尿液、血浆、心脏和肾脏进行生化和形态学分析。扎米卡司他诱导的交感神经下调降低了SHRs的高血压，对HR无观察到的影响。接受扎米卡司他治疗的SHRs的心脏与体重比更低，而两个SHR队列之间的体重和肾脏与体重比相似。扎米卡司他治疗的SHRs的24小时尿量减少，但尿蛋白排泄量和肌酐清除率保持不变。扎米卡司他治疗显著降低了血浆甘油三酯、游离脂肪酸和天冬氨酸转氨酶水平。与年龄匹配的正常血压Wistar-Kyoto大鼠相比，老年SHRs的血浆炎症标志物水平更高。与未治疗的SHRs相比，抑制DBH所获得的炎症益处表现为血浆中CRP、MCP-1、IL-5、IL-17α、GRO/KC、MIP-1α和RANTES水平降低。总之，抑制DBH可降低老年雄性SHRs的去甲肾上腺素水平，减少终末器官损伤，并改善心脏代谢和炎症生物标志物。
