Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, HM-1200 Medical College of Georgia, 1120 15th Street, Augusta, GA 30912-2450, USA. Charlie Norwood Veterans Administration Medical Center, Augusta, GA, USA.
Transl Stroke Res. 2011 Jun 1;2(2):179-85. doi: 10.1007/s12975-010-0061-1.
We have shown that reduction of blood pressure (BP) immediately after the onset of reperfusion reduced neurovascular damage and improved functional outcome after experimental cerebral ischemia and candesartan is particularly effective in improving long-term functional outcome. In this study, we sought to determine if early BP lowering with candesartan, in the presence of an occluded cerebral artery, will reduce injury and improve outcome after experimental stroke. Male Wistar rats underwent 24 h or 7 days of middle cerebral artery occlusion (MCAO). A single dose of 1 mg/kg candesartan was administered intravenously at 3 h after MCAO. Animals received neurobehavioral testing at 3 h, 24 h, and 7 days, and blood pressure was measured by telemetry. Animals had brain tissue collected for infarct size (24 h and 7 days), hemoglobin content, matrix metalloproteinase (MMP) activity, and vascular endothelial growth factor (VEGF) expression (24 h only). Candesartan significantly decreased blood pressure, infarct size (-20%; p=0.021), hemoglobin excess (-50%; p=0.0013), and edema (-35%; p=0.0005) at 24 h after MCAO. This resulted in a reduced cerebral perfusion deficit (p=0.034) in the ischemic hemisphere compared with saline and significantly improved Bederson scores and paw grasp. MMP-2, MMP-9, and VEGF were significantly increased by MCAO, but there were no differences between candesartan- and saline-treated animals. There were no significant differences in behavioral outcome at day 7. BP lowering with candesartan reduces early brain injury after experimental stroke even when the artery remains occluded. The early benefits were not sustained at 7 days, as seen in reperfused animals, however. The neuroprotection and neurorestorative properties of candesartan may occur by separate distinct mechanisms.
我们已经证明，再灌注即刻时血压（BP）的降低可减轻神经血管损伤，并改善实验性脑缺血后的功能预后，坎地沙坦尤其能有效改善长期功能预后。在这项研究中，我们试图确定在大脑中动脉闭塞（MCAO）的情况下，坎地沙坦早期降压是否会减轻实验性中风后的损伤并改善预后。雄性 Wistar 大鼠接受了 24 小时或 7 天的大脑中动脉闭塞（MCAO）。MCAO 后 3 小时静脉给予 1mg/kg 坎地沙坦单次剂量。动物在 3 小时、24 小时和 7 天时接受神经行为测试，并通过遥测法测量血压。动物在 24 小时和 7 天时采集脑组织用于梗死面积（24 小时和 7 天）、血红蛋白含量、基质金属蛋白酶（MMP）活性和血管内皮生长因子（VEGF）表达（仅 24 小时）。坎地沙坦在 MCAO 后 24 小时可显著降低血压、梗死面积（-20%；p=0.021）、血红蛋白过多（-50%；p=0.0013）和水肿（-35%；p=0.0005）。与盐水相比，这导致缺血半球的脑灌注缺损减少（p=0.034），并且显著改善了 Bederson 评分和爪抓握。MMP-2、MMP-9 和 VEGF 在 MCAO 后明显增加，但坎地沙坦和盐水治疗的动物之间没有差异。在第 7 天，行为结果没有明显差异。即使动脉仍然闭塞，坎地沙坦降低血压也可减轻实验性中风后的早期脑损伤。然而，在再灌注动物中，这种早期益处并未持续到 7 天。坎地沙坦的神经保护和神经修复特性可能通过单独的不同机制发生。
