低剂量坎地沙坦对小鼠脑梗死使用重组组织型纤溶酶原激活剂溶栓的出血并发症的影响及机制  

The effect and mechanism of low dose candesartan on hemorrhagic complications of thrombolytic therapy with recombinant tissue plasminogen activator after cerebral infarction

作　　者：冯晓燕 李蓉[2] 马涛[1] FENG Xiao-yan;LI Rong;MA Tao(Department of Neurology,Wuxi No.2 People's Hospital,Wuxi 214002,China)

机构地区：[1]无锡市第二人民医院神经内科,214002 [2]无锡市第二人民医院药剂科,214002

出　　处：《临床神经病学杂志》2020年第1期52-56,共5页Journal of Clinical Neurology

基　　金：江苏省“六个一工程”拔尖人才科研项目(LGY2017013)。

摘　　要：目的探讨低剂量坎地沙坦(Cand)对小鼠脑梗死用重组组织型纤溶酶原激活剂(rt-PA)溶栓出血并发症的影响及机制。方法160只小鼠随机分为对照组(56只)、rt-PA组(52只)、rt-PA+Cand组(52只)。用线栓法建立大脑中动脉栓塞(MCAO)模型,rt-PA组和rt-PA+Cand组在MCAO开始后2 h股静脉注射rt-PA(10 mg/kg),rt-PA+Cand组MCAO术前口服Cand 2周[0.5 mg/(kg·d)]。术后24 h评价各组神经功能、脑出血转化情况、出血转化体积及伊文思蓝渗出浓度,定量反转录聚合酶连锁反应法检测脑组织基质金属蛋白酶-9(MMP-9)、Claudin-5基因表达变化,免疫荧光法检测MMP-9、Claudin-5蛋白表达变化,Western blotting法检测脑组织血浆激肽释放酶(Pkal)、血管紧张素Ⅱ(AngⅡ)受体(AT1R)及缓激肽受体(B2R)蛋白表达变化。结果对照组及rt-PA+Cand组一般功能损伤评分、局灶功能损伤评分、出血转化评分、血红蛋白水平及伊文思蓝渗出浓度显著低于rt-PA组(均P<0.01)。与rt-PA组比较,对照组及rt-PA+Cand组MMP-9 mRNA相对表达量及阳性细胞率显著降低,Claudin-5 mRNA相对表达量及阳性细胞率显著升高(P<0.05~0.01)。对照组及rt-PA+Cand组Pkal、AT1R、B2R表达显著低于rt-PA组(P<0.05~0.01)。结论低剂量Cand可以一定程度上预防并减轻小鼠脑缺血再灌注后使用rt-PA的出血并发症,这可能是通过减少AngⅡ-AT1R/Pkal表达实现的。Objective To investigate the effect and mechanism of low dose candesartan(Cand)on hemorrhagic complications of thrombolytic therapy with recombinant tissue plasminogen activator(rt-PA)after cerebral infarction in mice.Methods One hundred and sixty mice were randomly divided into control group(56 mice),rt-PA group(52 mice),rt-PA+Cand group(52 mice).Middle cerebral artery occlusion(MCAO)models were established by thread embolization.At 2 hours after MCAO,rt-PA(10 mg/kg)was injected into femoral vein in rt-PA and rt-PA+Cand group,and rt-PA+Cand group was given oral Cand[0.5 mg/(kg·d)]for two weeks before MCAO.To evaluate the neural function,cerebral hemorrhagic transformation situation,hemorrhagic transformation volume and evans blue exudation concentration of mice in each group at 24 hours after MCAO.To detect the changes of MMP-9 and Claudin-5 gene expression of mice by quantitative reverse transcription polymerase chain reaction and the changes of protein expression by immunofluorescence in brain tissue of each group at 24 hours after MCAO.To detect the protein expression of plasma kallikrein(Pkal),bradykinin receptor(B2 R)and angiotensinⅡreceptor(AT1 R)by western blotting at 24 hours after MCAO.Results The general deficits scores,focal deficits scores,hemorrhagic transformation scores,hemoglobin and evans blue exudate concentration in control group and rt-PA+Cand group were significantly lower than those inrt-PA group(all P<0.01).Compared with those in rt-PA group,the relative expression of MMP-9 mRNA and the rate of positive cells in control group and rt-PA+Cand group were significantly decreased,while the relative expression of Claudin-5 mRNA and the rate of positive cells were significantly increased(P<0.05-0.01).The expression of Pkal,AT1 R and B2 R in control group and rt-PA+Cand group were significantly lower than those in rt-PA group(P<0.05-0.01).Conclusion Low dose candesartan can prevent and reduce rt-PA related hemorrhage after cerebral ischemia-reperfusion in mice,which may be achieved by reducing

关 键 词：脑梗死 缺血再灌注 出血转化 血浆激肽释放酶 重组组织型纤溶酶原激活剂 

分 类 号：R742.5[医药卫生—神经病学与精神病学]