Bralet J, Marie C, Mossiat C, Lecomte J M, Gros C, Schwartz J C
Faculté de Pharmacie, Laboratoire de Pharmacodynamie, Dijon, France.
J Pharmacol Exp Ther. 1994 Jul;270(1):8-14.
The aim of the study was to compare, in a rat model of congestive heart failure, the effect of captopril, a selective angiotensin-converting enzyme (ACE; EC 3.4.15.1) inhibitor, to that of alatriopril, a mixed inhibitor of ACE and atriopeptidase (EC 3.4.24.11), an enzyme implicated in the degradation of atrial natriuretic factor (ANF). Myocardial infarction was induced by ligation of the left coronary artery. Groups of rats received orally twice daily captopril (10 mg/kg), alatriopril (100 mg/kg) or vehicle. Treatments were started 18 to 20 h after ligation and continued for 4 weeks. Hypertrophic and hormonal changes reflecting congestive heart failure were assessed in rats with large infarcts by measuring the relative weight of cardiac tissues as well as by assaying ANF in heart and plasma and by measuring renin activity in plasma. Both treatments significantly reduced cardiac hypertrophy, but alatriopril showed a greater efficacy than captopril--the increase in relative heart weight reaching 38% with captopril and only 22% with alatriopril (P < .05). The hypertrophy of right ventricle was reduced by 47% with alatriopril and by 35% with captopril (N.S.), whereas the corresponding reductions for atria were 47% vs. 21% (P < .05). Both treatments prevented the ligation-induced increase of ANF level in the right ventricle. In contrast, plasma ANF level was significantly reduced after captopril but not after alatriopril treatment, a difference that probably reflects the protection of endogenous ANF in circulation resulting from atriopeptidase inhibition. Plasma renin was increased by 36-fold after captopril but only by 1.6-fold after alatriopril, a difference that presumably reflects the inhibition of renal renin secretion by endogenous ANF after alatriopril. These data suggest that enhancement of ANF levels in circulation via atriopeptidase inhibition magnifies the capacity of ACE inhibitors to prevent cardiac hypertrophy, and they show the potential therapeutic value of mixed ACE-atriopeptidase inhibitors in congestive heart failure.
本研究的目的是在充血性心力衰竭大鼠模型中，比较选择性血管紧张素转换酶（ACE；EC 3.4.15.1）抑制剂卡托普利与ACE和心房肽酶（EC 3.4.24.11，一种与心房利钠因子（ANF）降解有关的酶）混合抑制剂阿拉普利的效果。通过结扎左冠状动脉诱导心肌梗死。大鼠分组，每天口服两次卡托普利（10 mg/kg）、阿拉普利（100 mg/kg）或赋形剂。在结扎后18至20小时开始治疗，并持续4周。通过测量心脏组织的相对重量、检测心脏和血浆中的ANF以及测量血浆肾素活性，评估有大面积梗死的大鼠中反映充血性心力衰竭的肥厚和激素变化。两种治疗均显著减轻心脏肥大，但阿拉普利的疗效优于卡托普利——卡托普利治疗时心脏相对重量增加38%，而阿拉普利仅为22%（P < 0.05）。阿拉普利使右心室肥大减少47%，卡托普利减少35%（无统计学差异），而心房相应的减少分别为47%和21%（P < 0.05）。两种治疗均阻止了结扎诱导的右心室ANF水平升高。相反，卡托普利治疗后血浆ANF水平显著降低，而阿拉普利治疗后未降低，这种差异可能反映了由于心房肽酶抑制而对循环中内源性ANF的保护。卡托普利治疗后血浆肾素增加36倍，而阿拉普利仅增加1.6倍，这种差异可能反映了阿拉普利治疗后内源性ANF对肾素分泌的抑制。这些数据表明，通过抑制心房肽酶提高循环中ANF水平可增强ACE抑制剂预防心脏肥大的能力，并显示了ACE-心房肽酶混合抑制剂在充血性心力衰竭中的潜在治疗价值。
