广谱基质金属蛋白酶抑制剂对高血压性脑卒中影响的实验研究  

Effects of Doxycline,An Broad-Spectrum Matrix Metalloproteinases Inhibitor on the Morbidity and Mortality in Stroke-prone Spontaneously Hypertensive Rats

作　　者：涂悦[1] 周欣[2] 姚旻[2] 朱勇[2] 庞伟[2] 李玉明[2] 

机构地区：[1]中国人民武装警察部队医学院附属医院脑系科中心,天津300162 [2]中国人民武装警察部队医学院附属医院心血管病研究所,天津300162

出　　处：《中华高血压杂志》2006年第9期730-734,共5页Chinese Journal of Hypertension

基　　金：武警总部科研基金(WY2005-5);天津市科委重大科技攻关项目(No.023181411)资助

摘　　要：目的研究广谱基质金属蛋白酶抑制剂多西环素对卒中易感型自发性高血压大鼠(SHR-SP)脑血管系统基质金属蛋白酶的作用,探讨多西环素对脑卒中的发病率及病死率的影响。方法80只7周龄雄性SHR-SP大鼠随机分为药物干预组和对照组,每组再随机分为两个亚组,一个亚组用于观察脑卒中体征的发生情况,并比较两组脑卒中的发病率和病死率;采用明胶酶谱分析存活大鼠脑组织MMP-2和MMP-9活性,另一亚组进行血流动力学分析,且经氯化三苯基四唑氮(TTC)染色后用于分析脑卒中病灶的范围、数量和体积。结果(1)血流动力学分析显示多西环素组左心室+dp/dtmax、-dp/dtmin值较对照组增大[(15410.1±1679.2比对照组13684.1±1882.2和-10976.8±1372.6比对照组-9429.6±1840.9)mmHg/s,P<0.05]。(2)脑组织明胶酶谱分析显示多西环素组脑组织MMP-2活性较对照组降低。(3)大脑TTC染色结果显示多西环素组脑卒中病灶体积与对照组比较无显著性差异[(205.4±244.4比对照组167.1±274.3)mm3,P>0.05]。而多西环素组脑出血体积有大于对照组的趋势,但无统计学差异[(19.6±42.1比对照组3.4±5.0)mm3,P=0.176]。(4)多西环素组与对照组比较,脑卒中的病灶率(χ2=0.042)与病死率(χ2=0.135)无显著性差异(P>0.05)。结论多西环素可以抑制SHR-SP大脑中MMP-2活性,但在血压未控制时不能有效降低SHR-SP脑卒中发病率及脑卒中病灶体积。Objective To investigate the effects of doxycycline on cerebral matrix metalloproteinases （MMPs） in stroke-prone spontaneously hypertensive rats （SHR-SP） , and its contribution to stroke incidence, mortality rate and stroke volume in SHR-SP. Methods Eighty male SHR-SPs of 7 weeks old were randomly to receive doxycycline（30 mg/kg·d） or placebo. Each group was then randomly divided into 2 subgroups （n=20）. One subgroup was used for monitoring the behavioral signs of stroke and other for pathological study in brain. The incidence of stroke and the rate of mortality were compared by Kaplan-Meier survival analysis. The activity of MMP-2 and MMP-9 in brain were detected by gelatin-zymography. After hemodynamic analysis was performed, the brain samples of survival SHR-SPs were sectioned and stained in 0.05% 2, 3, 5-triphenyhetrazolium chloride （TTC）. Results （1）The haemodynamic analysis showed that left ventricular＋dp/dtmax and-dp/dtmin in doxycycline-treated group was higher than control animals（15410. 1±1679.2 vs 13684.1±1882. 2 and -10976.8±1372. 6 vs -9429.6±1840.9 mm Hg/s, P〈0.05）. （2）At 33 weeks of age, brain MMP-2 activity in doxycycline-treated group was markedly decreased compared with positive control; no MMP-9 activity was detected in symptoms free SHR-SPs. （3）The stroke lesion volume was similar in both groups （205.4±244.4 vs 167.1±274.3 mm^3 arbitrary units; P〉0. 05）. Nevertheless, doxycycline seemed slightly increased the volume of cerebral hemorrhage（ 19.6±42.1 vs placebo： 3.4±5.0 mm^3 , P=0. 176）. （4）Stroke-associated symptoms and mortality rate were similar between two groups（ the former X^2 = 0.042, the latter X^2 = 0.135, P〉0. 05）. Conclusion The results of present study show that, in the setting of uncontrolled blood pressure, MMPs inhibition by doxycycline can inhibit MMP-2 activity in the brain of SHR-SP, but not accompanied by decreased incidence of stroke attack and mortality rate. Lowering BP is the paramount strategy in decr

关 键 词：多西环素 基质金属蛋白酶 脑卒中 基质金属蛋白酶抑制剂 明胶酶谱分析 

分 类 号：R544.1[医药卫生—心血管疾病] R743.3[医药卫生—内科学]