Xu Jiang, Carretero Oscar A, Liu Yun-He, Yang Fang, Shesely Edward G, Oja-Tebbe Nancy, Yang Xiao-Ping
Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202-2689, USA.
J Card Fail. 2004 Feb;10(1):83-9.
Vasopeptidase inhibitors (VPi) may provide a new means of treating hypertension and congestive heart failure, because they simultaneously block angiotensin-converting enzyme (ACE) and neutral endopeptidase-24.11 (NEP-24.11), thereby inhibiting the renin-angiotensin system and enhancing vasodilator and natriuretic substances such as kinins and natriuretic peptides.
Using B(2) kinin receptor gene knockout mice (B(2)-/-), we tested the hypotheses that (1) VPi may provide better cardioprotection than ACE or NEP inhibitors alone (ACEi and NEPi) and (2) the effects of these inhibitors are partially mediated by kinins. Four weeks after myocardial infarction, B(2)-/- mice and B(2)+/+ mice were started on vehicle, ACEi (ramipril, 2.5 mg/kg/d), NEPi (candoxatril, 20 mg/kg/d) or VPi (omapatrilat, 50 mg/kg/d), which was continued for 20 weeks. Systolic blood pressure was measured weekly and cardiac function evaluated monthly by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were measured histopathologically.
We found that ACEi or NEPi improved cardiac function and remodeling and that these effects were more obvious in mice receiving VPi. Furthermore, the beneficial cardiac effects of ACEi, NEPi, and VPi were significantly attenuated in B(2)-/- mice. We concluded that dual inhibition of ACE and NEP with VPi provides better cardioprotection than ACEi or NEPi alone in mice with congestive heart failure induced by myocardial infarction, and these effects are mediated at least in part via kinins.
血管肽酶抑制剂（VPi）可能为治疗高血压和充血性心力衰竭提供一种新方法，因为它们能同时阻断血管紧张素转换酶（ACE）和中性内肽酶-24.11（NEP-24.11），从而抑制肾素-血管紧张素系统，并增强血管舒张剂和利钠物质，如激肽和利钠肽。
我们使用B(2)激肽受体基因敲除小鼠（B(2)-/-），检验以下假设：（1）与单独使用ACE或NEP抑制剂（ACEi和NEPi）相比，VPi可能提供更好的心脏保护作用；（2）这些抑制剂的作用部分由激肽介导。心肌梗死后四周，B(2)-/-小鼠和B(2)+/+小鼠开始接受赋形剂、ACEi（雷米普利，2.5mg/kg/天）、NEPi（坎多沙坦酯，20mg/kg/天）或VPi（奥美帕替，50mg/kg/天）治疗，并持续20周。每周测量收缩压，每月通过超声心动图评估心脏功能。通过组织病理学测量心肌细胞横截面积和间质胶原分数。
我们发现ACEi或NEPi可改善心脏功能和重塑，且这些作用在接受VPi的小鼠中更明显。此外，在B(2)-/-小鼠中，ACEi、NEPi和VPi的有益心脏作用显著减弱。我们得出结论，在心肌梗死诱导的充血性心力衰竭小鼠中，与单独使用ACEi或NEPi相比，VPi对ACE和NEP的双重抑制提供了更好的心脏保护作用，且这些作用至少部分通过激肽介导。
