冯 力, 唐秀玲, 王平安, 王剑波, 孙晓莉. 单硝酸异山梨醇乙酰阿魏酰胺的设计合成及对大鼠缺血心脏保护作用的研究[J]. 心脏杂志, 2012, 24(6): 696-701.
    引用本文: 冯 力, 唐秀玲, 王平安, 王剑波, 孙晓莉. 单硝酸异山梨醇乙酰阿魏酰胺的设计合成及对大鼠缺血心脏保护作用的研究[J]. 心脏杂志, 2012, 24(6): 696-701.
    shu
    Synthesis and protective effect of isosorbide mononitrate acetyl ferulate amide on ischemic myocardium in rats[J]. Chinese Heart Journal, 2012, 24(6): 696-701.
    Citation: Synthesis and protective effect of isosorbide mononitrate acetyl ferulate amide on ischemic myocardium in rats[J]. Chinese Heart Journal, 2012, 24(6): 696-701.
    shu

    单硝酸异山梨醇乙酰阿魏酰胺的设计合成及对大鼠缺血心脏保护作用的研究

    Synthesis and protective effect of isosorbide mononitrate acetyl ferulate amide on ischemic myocardium in rats

      摘要
    • 摘要: 目的:研制单硝酸异山梨醇乙酰阿魏酰胺（AcFA-201），并与阿魏酸钠（SF）、单硝酸异山梨醇酯（ISMN）和单硝酸异山梨醇乙酰阿魏酸酯（AFI）比较其对心肌缺血/再灌注（MI/R）大鼠心肌的保护作用。同时比较AcFA-201与AFI在模拟胃液中的稳定性。方法： 先将ISMN的羟基转化为胺基，再与乙酰化阿魏酰氯反应，生成新化合物AcFA-201。常规建立大鼠MI/R（30 min/3 h）模型，随机给予SF、ISMN、AFI或AcFA-201药物治疗。观察各组大鼠灌注末心功能恢复的情况，同时测定血清肌酸激酶（CK）、乳酸脱氢酶（LDH）、超氧化物歧化酶活性（SOD）、过氧化氢（H2O2）与丙二醛（MDA）的水平及NO的含量。结果： 合成路线可行，化合物AcFA-201的化学产率为81.8%。模拟胃液中的稳定性研究结果表明，AFI在给药10 min后，原药剩余很少，30 min完全消失；而AcFA-201在180 min后，基本保持初始给药浓度。与SF、ISMN治疗组相比，AcFA-201治疗组左室发展压、左室等容收缩压/舒张期压力上升或下降最大速率（±dp/dtmax）显著提高(n=8，P<0.05)。血清CK、LDH的活性和H2O2、MDA的含量降低而NO含量显著升高(n=8，P<0.05或P<0.01)；与AFI组相比，AcFA-201组各项指标均无显著性差异。结论： AcFA-201对MI/R损伤大鼠的心肌具有保护作用，其作用比SF、ISMN强，与AFI没有显著性差异。AcFA-201在模拟胃液中的稳定性明显优于AFI，更适合口服药物的研发。

       

      Abstract: AIM:To design and synthesize isosorbide mononitrate acetyl ferulate amide (AcFA-201) and to study the protective effect of AcFA-201 on myocardial ischemia/reperfusion (MI/R) injury in rats. We compared its effect with that of sodium ferulate (SF), isosorbide mononitrate (ISMN) and isosorbide mononitrate acetyl ferulic acid ester (AFI) and compared the stability of AFI and AcFA-201 in simulated gastric fluid. METHODS: We first translated the hydroxyl of ISMN into amino, caused it to react with acetylated ferulic oxychloride and then obtained AcFA-201 with chemical yield of 81.8%. Male Sprague Dawley rats were subjected to 30 min of myocardial ischemia and 3 h of reperfusion and then randomly received one of the following treatments separately: SF, ISMN, AFI or AcFA-201. The recovery of cardiac function was recorded and serum creatine kinase (CK) activity, lactate dehydrogenase (LDH) activity, superoxide dismutase (SOD) activity, hydrogen peroxide (H2O2) level, malondialdehyde (MDA) and nitric oxide (NO) content were determined at the end of reperfusion. RESULTS: Synthetic route was feasible and the chemical yield of AcFA-201 was 81.8%. Studies of the stability in simulated gastric fluid showed that little AFI remained after 10 min and disappeared in 30 min. Meanwhile, AcFA-201 retained the initial drug concentration even 180 min after dosing. Compared with SF and ISMN treatment groups, AcFA-201 treatment group significantly improved cardiac functions as evidenced by increasing left ventricular development pressure (LVDP) and ±dp/dtmax (n=8, P<0.05), reducing serum CK and LDH activities as well as H2O2 and MDA levels and obviously increasing NO content. However, no significant differences were observed between AcFA-201 group and AFI group. CONCLUSION: AcFA-201 showed a stronger cardioprotective effect against MI/R injury than SF and ISMN and there was no significant difference between AcFA-201 and AFI. AcFA-201 is more stable than AFI in simulated gastric fluid and AcFA-201 is thus more suitable for the development of oral drugs.

       

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