Marie C, Mossiat C, Gros C, Monteil T, Bralet J
Laboratoire de Pharmacodynamie, Faculté de Pharmacie, Dijon, France.
Cardiovasc Drugs Ther. 1996 Nov;10(5):593-8. doi: 10.1007/BF00051002.
Myocardial infarction was induced by rats by ligation of the left coronary artery. Treatment with TM1, a prodrug of SQ 28,603, an inhibitor of neutral endopeptidase (NEP, EC 3.4.24.11), was started 18-20 hours after ligation and was continued for 4 weeks (100 mg/kg, orally, twice daily). Morphological and biochemical parameters were assessed at the endo of therapy. The treatment resulted in a significant reduction of heart hypertrophy, which was restricted to the parts of myocardium hemodynamically upstream of the infarcted left ventricle. The weights of the right ventricle and atria were reduced by 15-20%, whereas the treatment had no effect on the left ventricle and septum weights. Treatment led to an almost complete inhibition of plasma NEP activity and to a slight decrease (-14%, p < 0.05) in plasma ACE activity. Plasma ANF level increased 3.8-fold after ligation, and treatment resulted in a slight ( + 29%) and nonsignificant additional increase in the ANF level. The amount of hydroxyproline in the right ventricle was enhanced by + 207% in control ligated rats and by +140% (NS) in treated rats. These data indicated that prolonged NEP inhibition exerts a favorable effect in heart failure by reducing the development of right ventricular and atrial hypertrophy. These effects may result from an improvement in hemodynamic conditions, leading to a reduction in cardiac preload.
通过结扎大鼠左冠状动脉诱导心肌梗死。在结扎后18 - 20小时开始用TM1（SQ 28,603的前体药物，中性内肽酶（NEP，EC 3.4.24.11）抑制剂）进行治疗，并持续4周（100mg/kg，口服，每日两次）。在治疗结束时评估形态学和生化参数。该治疗导致心脏肥大显著减轻，这种减轻仅限于梗死左心室血流动力学上游的心肌部分。右心室和心房重量减轻了15 - 20%，而该治疗对左心室和室间隔重量没有影响。治疗导致血浆NEP活性几乎完全受到抑制，血浆ACE活性略有下降（-14%，p < 0.05）。结扎后血浆心钠素（ANF）水平增加了3.8倍，治疗导致ANF水平略有（+29%）但无显著统计学意义的额外增加。在对照结扎大鼠中，右心室羟脯氨酸含量增加了207%，在治疗大鼠中增加了140%（无统计学意义）。这些数据表明，长期抑制NEP通过减少右心室和心房肥大的发展，对心力衰竭发挥有益作用。这些作用可能源于血流动力学状况的改善，导致心脏前负荷降低。
