Linz Wolfgang, Schäfer Stefan, Afkham Freni, Gerl Martin, Schmidts Hans-Ludwig, Rütten Hartmut
Therapeutic Department Cardiovascular Diseases, Sanofi Aventis Deutschland GmbH, Frankfurt am Main, Germany.
J Renin Angiotensin Aldosterone Syst. 2006 Sep;7(3):155-61. doi: 10.3317/jraas.2006.025.
Vasopeptidase inhibition has been shown to be an effective antihypertensive principle but its long-term effects on hypertensive target organ damage are not known. We investigated the myocardial, vascular and renal effects of chronic vasopeptidase inhibition in arterial hypertension.
One hundred and thirty-nine male spontaneously hypertensive rats aged 15 months were treated chronically with either the pure angiotensin-converting enzyme (ACE) inhibitor, ramipril (1 mg/kg/d in drinking water, n=46), or the vasopeptidase inhibitor AVE7688 (30 mg/kg/d in chow, n=46), or placebo (n=47) and followed up until they died. After six months, both ramipril and AVE7688 had markedly reduced plasma ACE activity, normalised blood pressure (BP), reduced left ventricular mass and improved systolic function to similar extents. Acetylcholine mediated relaxation of aortic rings was improved by both ramipril and AVE7688. There was substantial albuminuria in the placebo group (albumin-to-creatinine ratio 107+/-54 microg/mg), which was significantly reduced by ramipril to 57+/-34 microg/mg, and practically abolished in the AVE7688 group (22+/-12 microg/mg, p<0.05 vs. placebo and ramipril). Tubulo-interstitial damage (semi-quantitative score) was significantly reduced by AVE7688 and ramipril. Overall mortality was markedly reduced in the ramipril and AVE7688 groups (13% and 16% at six months, respectively), both p<0.05 vs. placebo (71%).
Vasopeptidase inhibition effectively controls BP and reduces myocardial, vascular and renal target organ damage, resulting in a markedly prolonged survival. At similar degrees of plasma ACE inhibition, AVE7688 compared to ramipril offers superior protection against hypertensive kidney damage.
血管肽酶抑制已被证明是一种有效的抗高血压原理，但其对高血压靶器官损害的长期影响尚不清楚。我们研究了慢性血管肽酶抑制在动脉高血压中对心肌、血管和肾脏的影响。
139只15月龄雄性自发性高血压大鼠长期接受以下处理：单纯血管紧张素转换酶（ACE）抑制剂雷米普利（饮水中1mg/kg/d，n = 46）、血管肽酶抑制剂AVE7688（饲料中30mg/kg/d，n = 46）或安慰剂（n = 47），并随访至死亡。6个月后，雷米普利和AVE7688均显著降低血浆ACE活性，使血压正常化，减轻左心室质量，并在相似程度上改善收缩功能。雷米普利和AVE7688均改善了乙酰胆碱介导的主动脉环舒张。安慰剂组有大量蛋白尿（白蛋白与肌酐比值为107±54μg/mg），雷米普利将其显著降低至57±34μg/mg，而AVE7688组几乎消除了蛋白尿（22±12μg/mg，与安慰剂和雷米普利相比，p<0.05）。AVE7688和雷米普利均显著降低了肾小管间质损伤（半定量评分）。雷米普利组和AVE7688组的总体死亡率显著降低（6个月时分别为13%和16%），两者与安慰剂组（71%）相比，p均<0.05。
血管肽酶抑制可有效控制血压，减少心肌、血管和肾脏靶器官损害，从而显著延长生存期。在血浆ACE抑制程度相似的情况下，与雷米普利相比，AVE7688对高血压肾脏损害提供了更好的保护。
