Milanez M C, Gomes M G, Vassallo D V, Mill J G
Department of Physiological Sciences, Federal University of Espirito Santo, Vitória, Brazil.
J Card Fail. 1997 Sep;3(3):189-97. doi: 10.1016/s1071-9164(97)90015-4.
Myocardial infarction is an important cause of heart failure because it cause tissue loss and contractility disturbances. In chronically infarcted hearts the increase in the collagen content in the extracellular matrix of the surviving viable myocardium has been considered a major factor contributing to development of heart failure. Postinfarction neuroendocrine activation involving the renin-angiotensin system has been implicated in this cardiac fibrosis.
As collagen synthesis and degradation are dynamic processes and postinfarction remodeling is a time-dependent phenomenon, rats submitted to coronary artery ligation to produce myocardial infarction were treated with captopril after infarction (30 mg/kg, intraperitoneally, daily) to investigate whether blockade of the renin-angiotensin system can prevent postinfarction myocardial hypertrophy and reactive fibrosis. Groups of rats with myocardial infarction were treated with captopril throughout the protocol period (6 weeks), or during the first 3 weeks after infarction (early therapy), or only during the last 3 weeks of the protocol (late therapy). Untreated groups of rats with or without myocardial infarction were used as control subjects. All animals were killed 6 weeks after surgery to evaluate hypertrophy of heart chambers and collagen deposition in the right ventricle wall and in surviving left ventricular muscle. Protein and hydroxyproline concentrations were assayed biochemically in these tissue homogenates. Only rats with an infarct covering 20 to 40% of the left ventricular surface were included in the study. In the control uninfarcted group (n = 12), hydroxyproline content was 152 +/- 12 micrograms in the right ventricle and 370 +/- 30 micrograms in the left ventricle. These values increased (P < .05) to 232 +/- 13 and 630 +/- 46 micrograms, respectively, in the group with myocardial infarction (n = 8) without treatment. These values were significantly reduced (P < .05) to 160 +/- 9 micrograms in the right ventricle and 520 +/- 40 micrograms in the left ventricle in the group with myocardial infarction treated with captopril for 6 weeks. The percentage decreases in collagen content and myocardial weight produced by captopril were similar. Thus, hydroxyproline concentration (mg hydroxyproline muscle), which increases significantly in both ventricles after myocardial infarction, was not modified by captopril therapy. Protein concentration in the right and left ventricular muscles decreased after myocardial infarction. This decrease was enhanced in the infarcted groups submitted to captopril treatment, mainly in the group treated for 6 weeks. Lesser effects on hypertrophy and hydroxyproline content were observed in the groups of rats treated with captopril in only the earlier or later phase of infarction.
It is concluded that captopril reduces similarly postinfarction hypertrophy and collagen deposition in surviving myocardium. These effects, although less intense, also occur when the drug is used for a short period immediately after myocardial infarction or when used later, when ventricular remodeling is almost fully developed.
心肌梗死是心力衰竭的重要原因，因为它会导致组织损失和收缩功能障碍。在慢性梗死心脏中，存活的有活力心肌细胞外基质中胶原蛋白含量的增加被认为是导致心力衰竭发展的主要因素。涉及肾素 - 血管紧张素系统的梗死后神经内分泌激活与这种心脏纤维化有关。
由于胶原蛋白的合成和降解是动态过程，且梗死后重塑是一种时间依赖性现象，对接受冠状动脉结扎以产生心肌梗死的大鼠在梗死后用卡托普利治疗（30mg/kg，腹腔注射，每日），以研究肾素 - 血管紧张素系统的阻断是否能预防梗死后心肌肥大和反应性纤维化。心肌梗死大鼠组在整个实验期（6周）、梗死后头3周（早期治疗）或仅在实验的最后3周（晚期治疗）接受卡托普利治疗。未治疗的有或无心肌梗死的大鼠组用作对照。所有动物在手术后6周处死，以评估心腔肥大以及右心室壁和存活左心室肌中的胶原蛋白沉积。对这些组织匀浆进行生化分析，测定蛋白质和羟脯氨酸浓度。仅纳入梗死面积覆盖左心室表面20%至40%的大鼠进行研究。在未梗死的对照组（n = 12）中，右心室羟脯氨酸含量为152±12μg，左心室为370±30μg。在未治疗的心肌梗死组（n = 8）中，这些值分别增加（P <.05）至232±13μg和630±46μg。在接受卡托普利治疗6周的心肌梗死组中，这些值显著降低（P <.05），右心室降至160±9μg，左心室降至520±40μg。卡托普利导致的胶原蛋白含量和心肌重量的降低百分比相似。因此，心肌梗死后两个心室中均显著增加的羟脯氨酸浓度（mg羟脯氨酸/肌肉）并未因卡托普利治疗而改变。心肌梗死后右心室和左心室肌中的蛋白质浓度降低。在接受卡托普利治疗的梗死组中，这种降低更为明显，主要是在治疗6周的组中。在仅在梗死早期或晚期接受卡托普利治疗的大鼠组中，观察到对肥大和羟脯氨酸含量的影响较小。
得出结论，卡托普利能类似地减轻梗死后存活心肌的肥大和胶原蛋白沉积。当药物在心肌梗死后立即短期使用或在心室重塑几乎完全发展后较晚使用时，这些作用虽然较弱，但同样会出现。
