局灶性脑缺血再灌注损伤大鼠脑内肾素-血管紧张素系统的变化及厄贝沙坦干预的影响

Changes of rennin-angiotensin system in rats with focal brain ischemia-reperfusion injury and the effects of intervention with Irbsartan

目的研究局灶性脑缺血再灌注大鼠脑内肾素-血管紧张素的变化,探讨厄贝沙坦干预的影响及其脑保护机制。方法将健康雄性SD大鼠随机分为假手术组、缺血再灌注(IR)组、厄贝沙坦预处理组(厄贝沙坦组)[30mg/(kg.d)连续灌胃3周]。用线栓法制作右侧大脑中动脉缺血再灌注模型,进行神经功能缺损程度评分,TCC染色法测定梗死体积,逆转录-聚合酶链反应方法测定脑组织和外周血白细胞血管紧张素Ⅱ1型受体(AT1R)和2型受体(AT2R) mRNA表达,放免法测定脑组织血管紧张素Ⅱ(AngⅡ)水平及肾素活性。结果(1)与IR组比较,厄贝沙坦组神经功能缺损程度评分显著改善,梗死体积减少。(2)再灌注后24h和72h,IR组大鼠的缺血侧和对侧皮质、下丘脑、脑干及外周血白细胞AT1R mRNA表达和AT2R mRNA表达均显著性高于假手术组(均P<0.01);而厄贝沙坦组IR后各时间点上述部位AT1R mRNA表达明显低于IR组(均P<0.01),AT2R mRNA表达高于IR组(均P<0.01)。(3)在IR后24h和72h,IR组大鼠脑组织和外周血AngⅡ水平、外周血肾素活性均显著性增高;厄贝沙坦组大鼠脑组织、外周血AngⅡ和肾素活性与IR组比较差异无统计学意义。结论脑缺血大鼠脑内AngⅡ、AT1R、AT2R表达增高,厄贝沙坦干预对脑缺血的神经保护作用可能与拮抗ATR、抑制ATRmRNA表达、上调ATR mRNA表达有关。

Objective To explore the changes of rennin-angiotensin system in rats with focal brain ischemiareperfusion injury and the effects of intervention and neuroprotective mechanisms with Irbsartan. Methods The male SD rats were randomly assigned to sham operated group, ischemia-reperfusion （IR） group and Irbsartan pretreatment group. The focal IR model was made by suture occlusion of right middle cerebral artery （MCAO）. At 24 h and 72 h following onset of MCAO with reperfusion, the neurologic impairment function scores and the infarction volume were evaluated, the mRNA expression of angiotensin Ⅱ type 1 receptor （ AT1 R） and angiotensin Ⅱ type 2 receptor（AT2R） were detected by RT-PCR, and Ang Ⅱ levels and Renin activity were examined by radioimmuno-assay. Results （ 1 ） Pretreatment with Irbsartan could significantly improve neurological outcome and reduced infarction size. （2） In bilateral cerebral cortex, hypothalamus, brain stem and peripheral blood leucocyte, the mRNA expressions of the AT1R and AT2 R were significantly increased after either 24 h or 72 h of MCAO with reperfusion （ all P 〈 0.01 ）. AT1R mRNA expression was down-regulated while AT2 R mRNA expression was up-regulated by pretreatment with Irbsartan in the above-mentioned areas （all P 〈 0. 01 ）. （3）Compared with the sham group, the levels of angiotensin Ⅱ in brain and peripheral blood as well as renin in peripheral blood in IR group were significantly elevated 24 h and 72 h after reperfusion, but there was no significantly different between Irbsartan group and IR groupt. Conclusions The Ang Ⅱ and expression of AT1R and AT2 R may elevate in rats with focal brain ischemia. Pretreatment with Irbsartan may play protective role on ischemic brain injury, and blocking AT1 R, down-regulating AT1R mRNA expressions and up-regulating AT2 R mRNA expression may be involved in the mechanisms.