一种抗心肌缺血/再灌注损伤的新化合物的合成及心肌保护作用研究
Synthesis and cardioprotective effect of a novel anti-ischemic / reperfused injury compound
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摘要:
在心肌缺血/再灌注 (MI/R) 时, 一氧化氮 (NO) 生成量减少, 氧自由基 (ROS) 大量堆积, 均可加重MI/R损伤。据此设计合成了可同时释放NO的ROS清除剂——乙酰阿魏单硝酸异山梨醇酯 (AFI), 并研究了AFI对MI/R大鼠的心肌保护作用及其作用机制。建立常规大鼠MI/R (30 min/3 h) 模型, 随机给予AFI (10 mg·kg-1)、阿魏酸 (40 mg·kg-1) 或单硝酸异山梨酯 (30 mg·kg-1) 药物治疗 (ig), 再灌注末检测大鼠心肌梗死面积和心功能指标, 同时测定血清肌酸激酶、乳酸脱氢酶、超氧化物歧化酶活性、过氧化氢与丙二醛水平及NO含量。与阿魏酸钠、单硝酸异山梨醇单独治疗组或联合治疗组相比, AFI治疗组心肌梗死面积显著减小 (n = 8, P < 0.01), 左室发展压、左室等容收缩/舒张期压力上升或下降最大速率显著提高 (n = 8, P < 0.05), 血清肌酸激酶和乳酸脱氢酶活性显著降低。与阿魏酸钠或单硝酸异山梨醇单独治疗组相比, AFI治疗组血清超氧化物歧化酶活性增加、过氧化氢与丙二醛含量降低而NO含量显著升高 (n = 8, P均< 0.05)。这些结果表明, AFI这一新化合物可减轻大鼠MI/R损伤, 具有保护心脏功能, 其心肌保护作用比阿魏酸钠、单硝酸异山梨醇的单独使用或联合使用均强。
Abstract:The aim of present study is to investigate the cardioprotective effect of a new compound acetyl ferulaic isosorbide (AFI), composed of ferulaic acid (FA) and isosorbide mononitrate (ISMN) by esterification in myocardial ischemia/reperfusion (MI/R). Male Sprague-Dawley rats, subjected to 30 minutes of myocardial ischemia and 3 hours of reperfusion, randomly received one of the following treatments separately: SHAM, I/R (MI/R + solvent), SF (MI/R+SF, 40 mg·kg-1, ig), ISMN (MI/R + ISMN, 30 mg·kg-1, ig), SF + ISMN (MI/R + SF + ISMN, 40 mg·kg-1 + 30 mg·kg-1, ig) and AFI (MI/R + AFI, 10 mg·kg-1, ig). Left ventricle developed pressures (LVDP) and the maximal first derivative of developed pressure (± dP/dtmax) were monitored throughout the experiments. Myocardial infarction size, serum creatine kinase (CK) activity, lactate dehydrogenase (LDH) activity, superoxide dismutase (SOD) activity, hydrogen peroxide (H2O2), malondialdehyde (MDA) and nitric oxide (NO) production were determined at the end of reperfusion. Compared with SF, ISMN or SF + ISMN treatment groups, AFI treatment decreased infarction size (n = 8, P < 0.01), improved cardiac function as evidenced by increased LVDP and ± dP/dtmax (n = 8, P < 0.05), increased serum SOD activity, reduced serum CK and LDH activities, H2O2 and MDA production (n = 8, P < 0.05). The new compound AFI showed a stronger cardioprotective effect against MI/R injury than SF, ISMN or their combined administration did.
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