Monash Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, VIC 3004, Australia; Department of Cardiology B, Oslo University Hospital Ullevål, Norway; Faculty of Medicine, University of Oslo, Norway.
Department of Cardiology B, Oslo University Hospital Ullevål, Norway; Faculty of Medicine, University of Oslo, Norway.
Pharmacol Ther. 2014 Oct;144(1):41-9. doi: 10.1016/j.pharmthera.2014.05.002. Epub 2014 May 14.
Cardiovascular diseases (CVD) continue to represent the major cause of death, morbidity and healthcare expenditure worldwide. Current medical therapy fails to effectively halt disease progression and to reduce adverse clinical outcomes, reflecting incomplete understanding of pathomechanisms as well as the need to expand current pharmacotherapeutic strategies. Hypertension and heart failure, the most important CVD entities, are associated with imbalance in neurohormonal systems activity such as the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system and the endothelin system. Blockade of the RAAS constitutes the most successful pharmacotherapeutic concept in hypertension and heart failure to date. The RAAS-opposing natriuretic peptide system constitutes the body's own BP-lowering system, and mediates a multitude of beneficial actions within cardiovascular tissues. The metallopeptidase neprilysin (NEP) hydrolyzes natriuretic peptides. Conceptually, NEP inhibition would increase salutary natriuretic peptide actions in CVD. However, stand-alone NEP inhibitors (NEPi) lacked efficacy beyond standard pharmacotherapy. Combined blockers of NEP and the endothelin system demonstrated efficacy in preclinical studies but have not been evaluated in clinical trials. A decade ago, omapatrilat and other dual-acting NEPi-ACEi (vasopeptidase-inhibitors) were promising agents for hypertension and heart failure. Despite greater efficacy, development of vasopeptidase-inhibitors was halted due to significant off-target effects in some cohorts, most notably increased frequency of angioedema in hypertensive subjects. Novel angiotensin-receptor-neprilysin-inhibitors (ARNi) seek to fully exploit clinical efficacy of combined RAAS-blockade and NEPi-mediated natriuretic peptide augmentation, and hopefully do so with improved clinical safety. We herein review current knowledge of NEPi as stand-alone and combined pharmacotherapeutic agents in hypertension and heart failure.
心血管疾病（CVD）仍然是全球主要的死亡原因、发病率和医疗保健支出。目前的医学治疗未能有效阻止疾病进展并降低不良临床结局，这反映了对发病机制的理解不完整，以及需要扩大当前的药物治疗策略。高血压和心力衰竭是最重要的 CVD 实体，与神经激素系统活性失衡有关，如肾素-血管紧张素-醛固酮系统（RAAS）、交感神经系统和内皮素系统。RAAS 阻断是迄今为止高血压和心力衰竭最成功的药物治疗概念。RAAS 拮抗的利钠肽系统构成了身体自身的降压系统，并介导心血管组织内的多种有益作用。金属肽酶 Neprilysin（NEP）水解利钠肽。从概念上讲，NEP 抑制会增加 CVD 中有益的利钠肽作用。然而，单独的 NEP 抑制剂（NEPi）在标准药物治疗之外缺乏疗效。NEP 和内皮素系统的联合抑制剂在临床前研究中表现出疗效，但尚未在临床试验中进行评估。十年前，Omapatrilat 和其他双重作用的 NEPi-ACEi（血管肽酶抑制剂）是高血压和心力衰竭的有前途的药物。尽管疗效更大，但由于某些队列中存在明显的脱靶效应，最显着的是高血压患者中血管水肿的频率增加，血管肽酶抑制剂的开发被停止。新型血管紧张素受体- Neprilysin 抑制剂（ARNi）试图充分利用联合 RAAS 阻断和 NEPi 介导的利钠肽增强的临床疗效，并希望在改善临床安全性的同时实现这一目标。我们在此回顾了 NEPi 作为单独和联合药物治疗剂在高血压和心力衰竭中的现有知识。
