The effects of blood pressure and urokinase on brain injuries after experimental cerebral infarction in rats
The effects of blood pressure and urokinase on brain injuries after experimental cerebral infarction in rats
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血压和尿激酶对实验性脑梗死大鼠脑损伤的影响
DOI：
10.1179/174313209x393924
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发表时间：
2009-03-01
影响因子：
1.9
通讯作者：
Luo, Yumin
中科院分区：
文献类型：
--
作者：
Ji, Xunming;Li, Ke;Luo, Yumin
摘要目的：随着半暗带理论的提出和动脉内溶栓（如尿激酶）的发展，缺血性脑血管病的预后得到了很大的改善。然而，出血性转化（HT）的发生率随之增加，一些研究表明血压与HT密切相关。血压和尿激酶对HT发生的影响机制尚不清楚。本研究观察了不同血压水平和尿激酶对大鼠脑缺血再灌注损伤、HT发生率及基质金属蛋白酶9（MMP-9）表达的影响。方法：采用血管腔内阻断法，在雄性Sprague-Dawley大鼠中诱导暂时性局灶性脑缺血。动物分为4组（每组11只）：低血压组（LP）、正常血压组（NP）、高血压组（HP）和尿激酶/高血压组（UKHP）。在再灌注开始时应用肾上腺素升高平均动脉血压（MABP）。MABP维持高于基线20 mmHg 1小时。硝普钠用于使MABP比基线降低20 mmHg，持续1小时。UKHP组同时使用尿激酶和肾上腺素。分别于再灌注后2 h（R2 h）和24 h（R24 h）进行神经功能缺损评分。所有大鼠均断头取脑，制成15 μ m厚切片，分析梗死体积和可见HT。每组取3只大鼠进行免疫组化和病理学分析。结果如下：基线时各组间MABP无显著性差异（p>0.05），但HP、UKHP和LP组血压明显升高和降低。各组在R2 h时的神经功能缺损评分无显著差异（p=0.443）。但在R24 h各组大鼠神经功能缺损评分差异有统计学意义，LP组大鼠神经功能缺损评分明显高于其他各组。与再灌注后2小时相比，LP组神经功能缺损评分恶化（p=0.047），但在再灌注后24小时，NP、HP和UKHP组改善（p分别为0.076、0.002、0.017）。HP组梗死体积明显小于LP组（p=0.006）。UKHP组HT发生率（42.8%）高于HP组（25%）和LP组（28.5%）。MMP-9在UKHP组大鼠脑缺血灶周围表达明显增加，在LP组和HP组大鼠脑皮质表达明显减少，但在基底节区表达无明显差异。结论：再灌注期间血压轻度升高可改善缺血再灌注大鼠的神经功能。HT的发生率随血压升高和尿激酶的应用而增加。免疫组化分析提示HT的发生可能与MMP-9的过度表达有关。
Abstract Objective: With the proposal of penumbra theory and development of intra-arterial thrombolysis (such as urokinase), the outcome of ischemic cerebrovascular disease is greatly improved. However, the incidence of hemorrhagic transformation (HT) increased concomitantly, and some studies showed a close relationship between blood pressure and HT. The mechanisms of blood pressure and urokinase effect on the incidence of HT are not clear. In this study, we investigated the effects of the different levels of blood pressure and urokinase on the ischemic lesions, the incidence of HT and the expression of matrix metalloproteinase 9 (MMP-9) in the rat ischemia–reperfusion models. Methods: Temporary focal ischemia was induced in male Sprague–Dawley rats using the intraluminal vascular occlusion method. The animals were assigned into four groups (n=11 in each group): low blood pressure group (LP), normal blood pressure group (NP), high blood pressure group (HP) and urokinase/high blood pressure group (UKHP). Adnephrin was applied to enhance the mean arterial blood pressure (MABP) at the beginning of reperfusion. MABP was maintained 20 mmHg higher than the baseline for 1 hour. Sodium nitroprusside was used to decrease MABP by 20 mmHg lower than the baseline for 1 hour. Both urokinase and adnephrin were used concomitantly in the UKHP group. Neurological deficit scores were evaluated at 2 hours (R2h) and 24 hours (R24h) after reperfusion. All rats were decapitated, their brains were sliced into 15-μm-thick slices, and the infarct volume and the visible HT were analysed. Three rats in each group were taken for immunohistochemistry and pathological analysis. Results: There was no significant difference in MABP among the groups at the baseline time points (p>0.05), but blood pressure are definitely increased and decreased in the HP, UKHP, and LP groups. Neurological deficit scores showed no significant difference at R2h among the groups (p=0.443). However, neurological deficit scores showed significant differences at R24h among the groups, the neurological deficits scores of rats in the LP group are significantly higher than that in the other groups. Compared with that of 2 hours after reperfusion, neurological deficit scores deteriorated in the LP group (p=0.047) but was improved in the NP, HP and UKHP groups (p=0.076, 0.002, 0.017, respectively) at 24 hours after reperfusion. The infarct volume in the HP group was apparently smaller than that in the LP group (p=0.006). There was indeed a tendency that HT occurred more frequently in the UKHP group (42.8%) than in the HP (25%) and LP (28.5%) groups. MMP-9 expression showed significant increase around the ischemic lesion areas of the UKHP group and significant decrease in the cortical areas of the LP and HP groups but no significant difference in the basal ganglia of rats of all groups. Conclusion: Mild elevation of blood pressure during reperfusion is supposed to improve neurological outcomes in rats following ischemia/reperfusion. The incidence of HT tended to increase with the elevation of blood pressure and the administration of urokinase. Immunohistochemitry analysis indicated that incidence of HT may correlate with excessive expression of MMP-9.