短期应用辛伐他汀对大鼠缺血再灌注后心肌无复流的影响及其潜在机制

Effects and potential mechanisms of short-term use of simvastatin on myocardial no-reflow after ischemia-reperfusion in rats

目的探讨辛伐他汀对缺血再灌注后心肌无复流的影响及其潜在机制。方法雄性Wistar大鼠48只，随机分为假手术组、对照组及辛伐他汀组。对照组及辛伐他汀组结扎左冠状动脉建立大鼠心肌无复流模型，假手术组仅开胸不结扎冠状动脉。术后进行缺血范围（RA／LVA）、无复流范围（NA／RA）及梗死范围（MIA／RA）评估，测定心肌组织内皮型一氧化氮合酶（eNOS）、诱导型一氧化氮合酶（iNOS）活性，一氧化氮（NO）含量、髓过氧化物酶（MPO）活性及丙二醛（MDA）含量，并用免疫组织化学法测定心肌组织及微血管核因子（NF）-kB p65阳性指数。结果在缺血范围差异无统计学意义的条件下，辛伐他汀组无复流范围显著小于对照组（34．10±7．05比52．09±6．89，P〈0．01），梗死范围也小于对照组（78．80±7．60比90．13±5．72，P〈0．05）。对照组及辛伐他汀组心肌组织iNOS活性、NO含量、MPO活性及MDA含量均高于假手术组，对照组eNOS活性显著低于假手术组（P 均〈0．05），辛伐他汀组eNOS活性与假手术组比较差异无统计学意义。辛伐他汀组心肌组织iNOS活性、NO含量、MPO活性及MDA含量均低于对照组（5．02±1．64比9．19±2．89，586．21±126．97比744．49±137．53，257．72±93．43比384．10±40．68．72．10±18．56比111．84±38．58，P均〈0．05），eNOS活性显著高于对照组（7．08±1．74比3．72±0．98，P〈0．01）。对照组及辛伐他汀组左心室游离壁梗死周边心肌细胞及微动脉NF·gBp65阳性指数均显著高于假手术组，辛伐他汀组低于对照组（21．59±10．5比34．32±9．55，27．27±13．19比44．91±15．06，P均〈0．05）。结论辛伐他汀可以改善缺血再灌注后心肌无复流，其可能机制是通过改善内皮功能，抑制炎症反应，进而抑制中性粒细胞的激活浸润，减少活性氧簇的生成，最终减轻无复流。

Objective The main objective of this study is to assess the the effect of simvastatin （sim） on myocardial no-reflow （NR） and explore the possible potential mechanisms. Methods Adult male Wistar rats were randomized into sham group （ n = 12）, I/R （90 rain ischemia via coronary ligation/120 rain reperfusion, n = 18） and I/R plus sim group （20 mg · kg^-1 · d^-1 sire pretreated via gavage beginning 3 days before I/R, n= 18）. After reperfusion, area at risk/area of left ventricular （RA/LVA）, area of NR, determined by the area not perfused by thioflavin-S/area at risk （NA/RA） and area of myocardial infarction/area at risk （MIA/RA） were measured. Myocardium homogenate was used to determine the activity of eNOS,iNOS and MPO, and the content of NO and MDA. Myocardial immunohistochemistry was performed to determine the positive index of NF-kB p65 in cardiomyocytes and arteriole. Results The NR and myocardial infarction areas in I/R plus sim group were significantly smaller than those in I/R group （34. 10 ±7.05 vs. 52.09 ±6. 89, 78.80 ±7.60 vs. 90. 13 ±5.72, each P 〈0.05） while the ischemia area was similar between the 2 groups （P 〉 0. 05）. The myocardial activities of iNOS and MPO, the contents of NO and MDA were significantly lower while eNOS activity was significantly higher in I/R plus sim group than those in I/R group （5.02 ±1.64 vs. 9.19 ±2.89, 586.21 ±126.97 vs. 744.49 ±137.53, 257.72 ± 93.43 vs. 384.10±40.68, 72.10±18.56 vs. 111.84±38.58, 7. 08±1.74 vs. 3.72±0.98, allP〈 0. 05 ）. The positive index of NF-±B p65 in cardiocytes and arteriole at left ventricular wall near the area of myocardial infarction was significantly lower in I/R plus sire group than that in I/R group （21.59 ± 10.5 vs.34.32±9.55, 27.27 ± 13.19 vs. 44.91 ± 15.06, each P 〈0.05）.Conclusion Simvastatin could improve myocardial NR after ischemia-reperfusion by attenuating endothelial dysfunction and inhibiting inflammation and neutrophil activation.