Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
Department of Medicine, Austin Health, The University of Melbourne, Victoria, Australia.
Heart. 2017 Oct;103(20):1569-1577. doi: 10.1136/heartjnl-2017-311295. Epub 2017 Jul 8.
Natriuretic peptides, especially B-type natriuretic peptide (BNP), have primarily been regarded as biomarkers in heart failure (HF). However, they are also possible therapeutic agents due to their potentially beneficial physiological effects. The angiotensin receptor-neprilysin inhibitor, sacubitril/valsartan, simultaneously augments the natriuretic peptide system (NPS) by inhibiting the enzyme neprilysin (NEP) and inhibits the renin-angiotensin-aldosterone system (RAAS) by blocking the angiotensin II receptor. It has been shown to improve mortality and hospitalisation outcomes in patients with HF due to left ventricular systolic dysfunction. The key advantage of sacubitril/valsartan has been perceived to be its ability to augment BNP, while its other effects have largely been overlooked. This review highlights the important effects of sacubitril/valsartan, beyond just the augmentation of BNP. First we discuss how NPS physiology differs between healthy individuals and those with HF by looking at mechanisms like the overwhelming effects of RAAS on the NPS, natriuretic peptide receptor desensitisation and absolute natriuretic deficiency. Second, this review explores other hormones that are augmented by sacubitril/valsartan such as bradykinin, substance P and adrenomedullin that may contribute to the efficacy of sacubitril/valsartan in HF. We also discuss concerns that sacubitril/valsartan may interfere with amyloid-β homeostasis with potential implications on Alzheimer's disease and macular degeneration. Finally, we explore the concept of 'autoinhibition' which is a recently described observation that humans have innate NEP inhibitory capability when natriuretic peptide levels rise above a threshold. There is speculation that autoinhibition may provide a surge of natriuretic and other vasoactive peptides to rapidly reverse decompensation. We contend that by pre-emptively inhibiting NEP, sacubitril/valsartan is inducing this surge earlier during decompensation, resulting in the better outcomes observed.
利钠肽，特别是 B 型利钠肽（BNP），主要被视为心力衰竭（HF）的生物标志物。然而，由于它们具有潜在的有益生理作用，因此它们也是可能的治疗药物。血管紧张素受体-脑啡肽酶抑制剂沙库巴曲缬沙坦通过抑制脑啡肽酶（NEP）同时增强利钠肽系统（NPS），并通过阻断血管紧张素 II 受体抑制肾素-血管紧张素-醛固酮系统（RAAS）。它已被证明可改善因左心室收缩功能障碍而导致 HF 的患者的死亡率和住院治疗结果。沙库巴曲缬沙坦的主要优势被认为是它能够增强 BNP，而其其他作用在很大程度上被忽视了。本综述重点介绍了沙库巴曲缬沙坦的重要作用，不仅仅是增强了 BNP。首先，我们通过研究 RAAS 对 NPS 的压倒性影响、利钠肽受体脱敏和绝对利钠肽缺乏等机制，讨论了健康个体和 HF 患者之间 NPS 生理学的差异。其次，本综述探讨了沙库巴曲缬沙坦增强的其他激素，如缓激肽、P 物质和肾上腺髓质素，这些激素可能有助于沙库巴曲缬沙坦在 HF 中的疗效。我们还讨论了沙库巴曲缬沙坦可能会干扰淀粉样蛋白-β的动态平衡的问题，这可能对阿尔茨海默病和黄斑变性有潜在影响。最后，我们探讨了“自动抑制”的概念，这是最近描述的一种观察结果，即当利钠肽水平升高超过阈值时，人类具有内在的 NEP 抑制能力。有人推测，自动抑制可能会迅速逆转失代偿，产生大量利钠肽和其他血管活性肽。我们认为，通过预先抑制 NEP，沙库巴曲缬沙坦在失代偿早期更早地诱导这种激增，从而导致观察到的更好结果。
