【摘要】 目的　研究苯妥英钠促进结缔组织增生的特殊药理作用对心肌梗死后组织修复的影响。方法　采用大鼠心肌梗死模型 ,分为苯妥英钠、卡托普利、苯妥英钠 +卡托普利、手术对照 (分为14天和 2 1天两组 )和假手术组 ;用苦味酸天狼猩红 偏振光法 ,对心室组织胶原沉积量、交联程度及分布情况进行定性及定量分析 ;并研究苯妥英钠不同浓度对大鼠心脏成纤维细胞增殖活性、转化生长因子 β1(TGF β1)与胶原合成量的影响以及巨噬细胞在其中发挥的作用。结果　苯妥英钠在体外对心脏成纤维细胞增殖活性无明显影响 ,但可通过激活巨噬细胞对心脏成纤维细胞的增殖活性、TGF β1与胶原合成量产生正性影响 ,并具有一定量效关系 (r =0 86 5和r =0 816 ,P <0 0 5 ) ;苯妥英钠可使梗死区胶原交联程度明显增高 ,并可增加Ⅰ /Ⅲ型胶原比值 ,均达到与心肌梗死后 2 1天相当的水平 ,而对非梗死区无明显影响。结论　苯妥英钠可以促进心肌梗死后梗死区的组织修复过程 ,对非梗死区胶原代谢无明显影响 ,具有潜在的临床应用价值。更多还原

【Abstract】 Objective To investgate the connective tissue proliferating characteristics of phenytoin in the wound healing process after acute myocardial infarction. Methods In vivo the study was performed on rat model of acute myocardial infarction. Surviving rat were randomly divided into different treatment groups: phenytoin (100 mg·kg -1 ·day -1 ip), captopril (2 g/L in dinking water ad libitum ),phenytoin plus captopril, operation control and sham operation. On day 14 after operation ( half of the controls were killed on day 21 ), rats were sacrificed. Hearts were removed and prepared for histological analysis. Picrosirius red staining plus polarized light microscopy were used for qualitative and quantitative analysis of collagen accumulation, cross linking in infarcted and non infarcted region of heart tissue slides. Neonatal rat cardiac fibroblast and adult rat peritoneal macrophage primary culture were performed as in vitro part. We tested the effects of phenytoin concentration gradient (0 μg/ml, 1 25 μg/ml, 2 5 μg/ml, 5 0 μg/ml, 10 0 μg/ml, 20 0 μg/ml) in culture media on cellular toxicity, proliferation, TGF β 1 production and soluble collagen secretion of cardiac fibroblast and studied the possible mechanisms mediated by macrophage, using the ELISA, MTT and biochemical assay. Results Phenytoin had little direct effects on neonatal rat cardiac fibroblast proliferation and extracellular matrix synthesis abilities in vitro , but pre stimulated macrophage by phenytoin can exert a positive influence on cardiac fibroblast bioactivities and present a dose dependent manner ( r =0 865 and r =0 816, P <0 05). Phenytoin could increase collagen intermolecular cross linking level [Phenytoin 130 19±12 09 vs operation control 111 44±10 33 (gray scales), P <0 01] and ratio of typeⅠ/Ⅲ collagen in the infarcted region, which was comparable to those of 21 days after myocardial infarction. Notably, phenytoin had little effect on collagen volume fraction, subtype ratio and distribution in non infarcted region. Conclusion For the first time, we demonstrated that by indirectly stimulating effects on macrophage, phenytoin could hasten the healing process in the infarcted region and had no obviously detrimental influence on collagen accumulation in non infarcted septum and right ventricle in our investigating period, which implied potential benefits on patients undergoing early post infarction ventricular remodeling process.更多还原