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目的:探讨阻断血管紧张素Ⅱ1型受体对动脉粥样硬化小鼠脑缺血再灌注损伤的影响。方法:实验于2003-09/2004-12在南方医科大学中心实验室完成。选择载脂蛋白E基因敲除小鼠40只,随机分为对照组(n=20):高胆固醇食物喂养10周,替米沙坦预处理组(n=20):高胆固醇食物饲喂8周后替咪沙坦0.3mg/(kg·d)拌入食物中连续饲喂2周。喂养10周后同时建立缺血/再灌注脑损伤模型,缺血1h,再灌注23h。行相关指标的测定:用尾袖法测量血压;图像分析系统计算梗死面积百分比;计算两组动物死亡率;神经功能损害评分如下:0分为无神经功能损害体征,1分为右前爪肌力减弱,2分为躯体向左侧弯曲,3分为向左侧作旋转运动,4分为无自主运动;行脑组织含水量测定;在荧光显微镜下观察超氧化物阴离子的产生情况。结果:剔除实验结束前死亡动物,对照组死亡5只,替咪沙坦预处理组死亡4只。对照组15只和替咪沙坦处理组16只计入结果。①替咪沙坦预处理对动物血压的影响:与对照组比较,缺血前、后及再灌注后替咪沙坦预处理对动物血压无明显影响犤(101±3),(105±5)mmHg;(87±6),(88±3)mmHg;(93±5),(94±6)mmHg,P>0.05犦。②替咪沙坦预处理对梗死面积的影响:缺血/再灌注损伤后可见恒定的白色梗死灶,与对照组相比,替咪沙坦预处理组梗死面积减小,差异显著(P<0.05)。③替咪沙坦预处理对动物死亡率、神经功能缺陷评分和脑组织含水量的影响:与对照组相比,替咪沙坦预处理能降低动物死亡率及神经功能缺陷评分和脑含水量犤46.67%,31.13%;2.75±0.20,2.00±0.30;(83.29±0.45)%,(80.17±0.32)%,P<0.05犦。④替咪沙坦预处理对脑血流的影响:中脑动脉梗死后,梗死灶中心区脑血流均降至基线值20%以下,再灌注后预处理组脑血流高于对照组(P<0.05)。而梗死灶半暗区脑血流均降至基线值50%以下,梗死后30min至再灌注后,预处理组脑血流高于对照组(P<0.05)。⑤替咪沙坦预处理对氧应激的影响:梗死灶活性氧的产生增加,替咪沙坦预处理组活性氧的产生不明显。替咪沙坦预处理组还原型辅酶Ⅱ的活性较对照组明显减低犤(0.512±0.030),(0.782±0.032)mkat/g,P<0.05犦。结论:预先阻断血管紧张素Ⅱ1型受体可以缩小动脉粥样硬化小鼠脑缺血再灌注损伤的梗死面积,降低脑水肿和动物死亡率,改善神经功能缺失体征,抑制超氧化物阴离子的产生和还原型辅酶Ⅱ氧化酶活性增加,从而减轻了脑损害的程度。
Objective: To investigate the effect of blocking angiotensin Ⅱ type 1 receptor on focal cerebral ischemia-reperfusion injury in atherosclerotic mice. Methods: The experiment was performed in the Central Laboratory of Southern Medical University from September 2003 to December 2004. Forty mice with apolipoprotein E knockout mice were randomly divided into control group (n = 20): high cholesterol diet for 10 weeks, telmisartan pretreatment group (n = 20): high cholesterol diet fed 8 Mice were fed with 0.3 mg / (kg · d) of imazalil for two weeks. After 10 weeks of feeding, a model of ischemia / reperfusion injury was also established. The rats were subjected to ischemia for 1 hour and then to reperfusion for 23 hours. Line-related indicators were measured: tail cuff method for measuring blood pressure; image analysis system to calculate the percentage of infarcted area; calculated two groups of animal mortality; neurological impairment score as follows: 0 points for no signs of neurological impairment, 1 for the right forepaw muscle strength Weakened, 2 points for the body to the left bending, 3 points for the left to make rotational movement, 4 points for no involuntary movement; line brain water content determination; observed under a fluorescence microscope superoxide anion production. Results: Five animals died in the control group and four died in the pretreatment group. Fifteen in the control group and 16 in the treatment group were included in the results. (1) The effect of pretreatment with miasartan on blood pressure in rats: Compared with the control group, pretreatment with bemisartan did not affect the blood pressure of the animals pre-and post-ischemia (101 ± 3), (105 ± 5) ) mmHg; (87 ± 6), (88 ± 3) mmHg; (93 ± 5), (94 ± 6) mmHg, P> 0.05 犦. ② The influence of pretreatment with imisartan on the infarct area: A constant white infarct was observed after ischemia / reperfusion injury. Compared with the control group, infarct size in the pretreatment group decreased significantly (P < 0.05). ③ The effects of premedication with bemisartan on animal mortality, neurological deficit scores and water content of brain tissue: Compared with the control group, pretreatment with bemisartan could reduce animal mortality and neurological deficit scores and brain water content犤 46.67%, 31.13%; 2.75 ± 0.20,2.00 ± 0.30; (83.29 ± 0.45)%, (80.17 ± 0.32)%, P <0.05 犦. ④ Effects of pretreatment with mimosartan on cerebral blood flow: Cerebral blood flow in the infarct center decreased to below 20% of baseline after infarction of middle cerebral artery. Cerebral blood flow of pretreatment group was higher than that of control group after reperfusion P <0.05). Cerebral blood flow in the penumbral area of infarction decreased to below 50% of the baseline value. After 30 min of infarction, the cerebral blood flow of the pretreatment group was higher than that of the control group (P <0.05). ⑤ the impact of pretreatment with imidacartan on oxygen stress: the production of reactive oxygen species increased infarction, reactive oxygen species generated for the pretreatment group of imidacloprid was not obvious. The activity of reduced coenzyme Ⅱ in the pretreatment group was significantly lower than that in the control group (12 (0.512 ± 0.030), (0.782 ± 0.032) mkat / g, P <0.05 犦). Conclusion: Blocking angiotensin Ⅱ type 1 receptor in advance can reduce infarct size, reduce cerebral edema and animal mortality in atherosclerotic mice with cerebral ischemia-reperfusion injury, improve signs of neurological deficits, and inhibit superoxide anion Produced and reduced coenzyme Ⅱ oxidase activity increased, thereby reducing the extent of brain damage.