Sheth Tej, Parker Tom, Block Alan, Hall Christian, Adam Albert, Pfeffer Mark A, Stewart Duncan J, Qian Chunlin, Rouleau Jean L
Division of Cardiology, University of Toronto and University Health Network, Toronto, Ontario, Canada.
Am J Cardiol. 2002 Sep 1;90(5):496-500. doi: 10.1016/s0002-9149(02)02521-3.
Angiotensin-converting enzyme (ACE) inhibitors exert their effects by modulating the neurohumoral milieu. Vasopeptidase inhibitors (VPI) are ACE and neutral endopeptidase inhibitors and may increase natriuretic peptides, bradykinin, and perhaps endothelin-1 in patients with congestive heart failure. Patients (n = 107) with ischemic or dilated cardiomyopathy, New York Heart Association functional class II to III, with left ventricular ejection fraction <40%, and on ACE inhibitor therapy were randomized to either the VPI omapatrilat 40 mg/day or the ACE inhibitor lisinopril 20 mg/day. Trough levels of neurohormones (24 hours after dosing) were assessed at baseline, and at 12 and 24 weeks of follow-up. C-terminal atrial natriuretic peptide (C-ANP) levels decreased with lisinopril (p = 0.035), but not with omapatrilat. In contrast, N-terminal ANP levels did not change, and brain natriuretic peptide (BNP) levels tended to decrease similarly in both groups. Endothelin-1 levels increased in both groups, the increase reaching statistical significance with omapatrilat (p = 0.008). Levels of the proinflammatory cytokine interleukin-6 tended to decrease, and the anti-inflammatory cytokine interleukin-10 increased in both groups, with statistical significance only for interleukin-10 with omapatrilat therapy. Neither agent changed catecholamines or angiotensin II. Thus, even at trough levels, omapatrilat potentiates C-ANP more than lisinopril. Potentially important effects of omapatrilat on endothelin-1 and anti-inflammatory cytokines were identified, providing potential explanations for differences in clinical outcome.
血管紧张素转换酶（ACE）抑制剂通过调节神经体液环境发挥作用。血管肽酶抑制剂（VPI）是ACE和中性内肽酶抑制剂，在充血性心力衰竭患者中可能会增加利钠肽、缓激肽，或许还有内皮素-1。患有缺血性或扩张型心肌病、纽约心脏协会心功能分级为II至III级、左心室射血分数<40%且正在接受ACE抑制剂治疗的患者（n = 107）被随机分为两组，一组每日服用40 mg的VPI奥美沙坦酯，另一组每日服用20 mg的ACE抑制剂赖诺普利。在基线以及随访的12周和24周时评估神经激素的谷值水平（给药后24小时）。使用赖诺普利后C末端心房利钠肽（C-ANP）水平降低（p = 0.035），而使用奥美沙坦酯后未降低。相比之下，N末端ANP水平没有变化，两组中脑利钠肽（BNP）水平也有类似的降低趋势。两组内皮素-1水平均升高，使用奥美沙坦酯时升高具有统计学意义（p = 0.008）。两组中促炎细胞因子白细胞介素-6水平有降低趋势，抗炎细胞因子白细胞介素-10水平升高，仅在使用奥美沙坦酯治疗时白细胞介素-10升高具有统计学意义。两种药物均未改变儿茶酚胺或血管紧张素II。因此，即使在谷值水平，奥美沙坦酯对C-ANP的增强作用也大于赖诺普利。已确定奥美沙坦酯对内皮素-1和抗炎细胞因子具有潜在的重要作用，这为临床结果的差异提供了潜在的解释。
