Neprilysin Inhibitors and Bradykinin.
Neprilysin Inhibitors and Bradykinin.
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DOI：
10.3389/fmed.2018.00257
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发表时间：
2018
影响因子：
3.9
通讯作者：
Campbell DJ
中科院分区：
文献类型：
--
作者：
Campbell DJ
缓激肽具有重要的生理作用，与调节血管张力和肾功能，保护缺血再灌注损伤有关。然而，缓激肽也有助于病理状态，如血管性水肿和炎症。缓激肽由许多不同的肽酶代谢，这些肽酶在缓激肽水平的控制中起主要作用。肽酶抑制剂疗法如血管紧张素转化酶（ACE）和脑啡肽酶抑制剂增加缓激肽水平，并且此类疗法的挑战是实现有益的心血管和肾脏作用而没有不良后果如可能由缓激肽水平增加引起的血管性水肿。脑啡肽酶也代谢利钠肽。然而，尽管增加利钠肽和缓激肽水平的潜在治疗益处，脑啡肽酶抑制剂治疗在原发性高血压和心力衰竭中仅具有适度的疗效。最初尝试将脑啡肽酶抑制与肾素血管紧张素系统抑制相结合，导致了奥马曲拉（omapatrilat）的开发，奥马曲拉是一种结合ACE和脑啡肽酶抑制的药物。然而，与ACE抑制剂依那普利（0.68%）相比，奥马曲拉在高血压患者中产生了不可接受的高血管性水肿发生率（2.17%），尽管奥马曲拉治疗的射血分数降低（HFrEF）心力衰竭患者的血管性水肿发生率较低（0.8%），与依那普利治疗（0.5%）无差异。最近，LCZ 696，一种结合血管紧张素受体阻滞剂和脑啡肽酶抑制剂的药物，被批准用于治疗HFrEF。LCZ 696治疗HFrEF的批准代表了长期脑啡肽酶抑制剂给药的首次批准。虽然接受LCZ 696治疗的HFrEF患者的血管性水肿发生率较低（0.45%），但LCZ 696治疗其他疾病（如高血压）是否也伴有可接受的血管性水肿发生率仍有待观察。
Bradykinin has important physiological actions related to the regulation of blood vessel tone and renal function, and protection from ischemia reperfusion injury. However, bradykinin also contributes to pathological states such as angioedema and inflammation. Bradykinin is metabolized by many different peptidases that play a major role in the control of bradykinin levels. Peptidase inhibitor therapies such as angiotensin converting enzyme (ACE) and neprilysin inhibitors increase bradykinin levels, and the challenge for such therapies is to achieve the beneficial cardiovascular and renal effects without the adverse consequences such as angioedema that may result from increased bradykinin levels. Neprilysin also metabolizes natriuretic peptides. However, despite the potential therapeutic benefit of increased natriuretic peptide and bradykinin levels, neprilysin inhibitor therapy has only modest efficacy in essential hypertension and heart failure. Initial attempts to combine neprilysin inhibition with inhibition of the renin angiotensin system led to the development of omapatrilat, a drug that combines ACE and neprilysin inhibition. However, omapatrilat produced an unacceptably high incidence of angioedema in patients with hypertension (2.17%) in comparison with the ACE inhibitor enalapril (0.68%), although angioedema incidence was less in patients with heart failure with reduced ejection fraction (HFrEF) treated with omapatrilat (0.8%), and not different from that for enalapril therapy (0.5%). More recently, LCZ696, a drug that combines angiotensin receptor blockade and neprilysin inhibition, was approved for the treatment of HFrEF. The approval of LCZ696 therapy for HFrEF represents the first approval of long-term neprilysin inhibitor administration. While angioedema incidence was acceptably low in HFrEF patients receiving LCZ696 therapy (0.45%), it remains to be seen whether LCZ696 therapy for other conditions such as hypertension is also accompanied by an acceptable incidence of angioedema.
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影响因子：
158.5
作者：
Bas, Murat;Greve, Jens;Hoffmann, Thomas K.
通讯作者：
Hoffmann, Thomas K.
影响因子：
37.8
作者：
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