Selective Inhibition of the C-Domain of ACE (Angiotensin-Converting Enzyme) Combined With Inhibition of NEP (Neprilysin): A Potential New Therapy for Hypertension.
Selective Inhibition of the C-Domain of ACE (Angiotensin-Converting Enzyme) Combined With Inhibition of NEP (Neprilysin): A Potential New Therapy for Hypertension.
复制标题
选择性抑制血管紧张素转换酶C结构域联合抑制NEP：一种潜在的高血压新疗法
DOI：
10.1161/hypertensionaha.121.17041
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Touyz RM
中科院分区：
文献类型：
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作者：
Alves-Lopes R;Montezano AC;Neves KB;Harvey A;Rios FJ;Skiba DS;Arendse LB;Guzik TJ;Graham D;Poglitsch M;Sturrock E;Touyz RM
补充数字内容可在文本中找到。中性内肽酶（NEP）和血管紧张素转换酶（ACE）的联合抑制，没有不良反应，仍然是心血管药物中有吸引力的治疗策略。奥马曲拉是一种双重NEP底物-ACE抑制剂，是一种有前途的抗高血压药物，但由于血管性水肿而在试验中失败，血管性水肿可能是由ACE的N-和C-结构域抑制引起的。在这里，我们的目的是确定是否赖诺普利-色氨酸（lisW-S），一个C-结构域特异性ACE抑制剂，保留N-结构域催化活性，与沙库巴曲（NEP抑制剂），差异影响心血管功能和血管通透性的高血压与omapatrilat和赖诺普利+沙库巴曲，抑制ACE的C-和N-结构域。Ang II（血管紧张素II）依赖性高血压小鼠（在肝脏中表达活性人肾素[也称为LinA 3]的转基因小鼠）接受溶媒、沙库巴曲、lisW-S、赖诺普利、赖诺普利+沙库巴曲或lisW-S+沙库巴曲4周。LinA 3小鼠的收缩压升高，沿着心脏肥大/功能障碍、内皮依赖性血管舒张受损、过度收缩反应、血管重塑和肾脏炎症。LisW-S+沙库巴曲、赖诺普利+沙库巴曲和奥马曲拉降低了LinA 3小鼠的收缩压，并使心血管重塑和血管过度收缩反应正常化。虽然赖诺普利+沙库巴曲和奥马曲拉改善乙酰胆碱诱导的血管舒张，lisW-S+沙库巴曲没有影响。内皮渗透性（伊文思蓝评估）在奥马曲拉中增加，但在LisW-S+沙库巴曲治疗的小鼠中没有增加。总之，lisW-S联合沙库巴曲降低了LinA 3小鼠的收缩压，改善了心功能障碍，与omapatrilat相似，但对内皮依赖性血管舒张没有影响。此外，在用lisW-S+沙库巴曲处理的小鼠中，奥马曲拉诱导的血管渗漏（血浆外渗）增加不明显。靶向ACE C-结构域和NEP作为联合治疗在降低收缩压方面可能与omapatrilat一样有效，但不会诱导血管通透性和内皮损伤。
Supplemental Digital Content is available in the text. Combined inhibition of NEP (neutral endopeptidase) and ACE (angiotensin-converting enzyme), without unwanted effects, remains an attractive therapeutic strategy in cardiovascular medicine. Omapatrilat, a dual NEP inhibitor–ACE inhibitor, was a promising antihypertensive drug but failed in trials due to angioedema, an effect possibly caused by inhibition of both the N- and C-domains of ACE. Here, we aimed to determine whether lisinopril-tryptophan (lisW-S), a C-domain specific ACE inhibitor that preserves the N-domain catalytic activity, together with sacubitril (NEP inhibitor), differentially influences cardiovascular function and vascular permeability in hypertension compared with omapatrilat and lisinopril+sacubitril which inhibits both the ACE C- and N-domains. Ang II (angiotensin II)–dependent hypertensive mice (transgenic mice expressing active human renin in the liver [also known as LinA3]) received vehicle, sacubitril, lisW-S, lisinopril, lisinopril+sacubitril, or lisW-S+sacubitril for 4 weeks. Systolic blood pressure was increased in LinA3 mice, along with cardiac hypertrophy/dysfunction, impaired endothelium-dependent vasorelaxation, hypercontractile responses, vascular remodeling, and renal inflammation. LisW-S+sacubitril, lisinopril+sacubitril, and omapatrilat reduced systolic blood pressure and normalized cardiovascular remodeling and vascular hypercontractile responses in LinA3 mice. Although lisinopril+sacubitril and omapatrilat improved Ach-induced vasorelaxation, lisW-S+sacubitril had no effect. Endothelial permeability (Evans Blue assessment) was increased in omapatrilat but not in LisW-S+sacubitril–treated mice. In conclusion, lisW-S combined with sacubitril reduced systolic blood pressure and improved cardiac dysfunction in LinA3 mice, similar to omapatrilat but without effects on endothelium-dependent vasorelaxation. Moreover, increased vascular leakage (plasma extravasation) induced by omapatrilat was not evident in mice treated with lisW-S+sacubitril. Targeting ACE C-domain and NEP as a combination therapy may be as effective as omapatrilat in lowering systolic blood pressure, but without inducing vascular permeability and endothelial injury.