Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University School of Medicine, Kagawa, Japan.
J Hypertens. 2011 Nov;29(11):2210-9. doi: 10.1097/HJH.0b013e32834bbb30.
Neurovascular protection against cerebral ischemia is not consistently observed with a postischemia hypotensive dose of candesartan. The aim of this study was to determine the levels of brain angiotensin II after reperfusion and the efficacy and therapeutic time window of postischemic treatments with hypotensive doses of candesartan for the treatment of cerebral ischemia.
Occlusions of the right middle cerebral artery (60 min) followed by reperfusion were performed using the thread method under halothane anesthesia in Sprague-Dawley (SD) rats. Protein levels of brain angiotensin II and mRNA levels of renin-angiotensin system components were evaluated following reperfusion (n=184 in total). Low-dose or high-dose treatments with candesartan cilexetil (1 or 10 mg/kg per day, respectively) were administered orally immediately following reperfusion once daily for 4 or 7 days (n = 119 in total). An additional group was treated with low-dose candesartan cilexetil after a 12-h delay based on the brain angiotensin II levels (n = 14).
Levels of brain angiotensin II transiently increased 4-12 h after reperfusion, which followed an increase in angiotensinogen mRNA. Candesartan cilexetil treatments significantly reduced blood pressure (BP) in rats administered the high dose and moderately in rats receiving the low dose. A low dose of candesartan cilexetil reduced the infarct size, cerebral edema, and neurological deficits, whereas the high-dose treatments showed limited reductions. Furthermore, oxidative stress following reperfusion was reduced with the low-dose treatments. The therapeutic time window was open for at least 12 h after reperfusion when brain angiotensin II levels had peaked.
Postischemic treatments using low hypotensive doses of candesartan cilexetil provided protection against cerebral ischemic injury and may have a clinically relevant therapeutic time window.
在缺血后低血压剂量的坎地沙坦中并未一致观察到对脑缺血的神经血管保护作用。本研究的目的是确定再灌注后脑组织血管紧张素 II 的水平以及缺血后用低血压剂量坎地沙坦治疗的疗效和治疗时间窗，用于治疗脑缺血。
在氟烷麻醉下通过线栓法在 Sprague-Dawley（SD）大鼠中进行右大脑中动脉闭塞（60 分钟），随后再灌注。在再灌注后评估脑组织血管紧张素 II 的蛋白水平和肾素-血管紧张素系统成分的 mRNA 水平（总共 184 例）。在再灌注后立即口服给予坎地沙坦西酯低剂量或高剂量治疗（分别为 1 或 10 mg/kg/天，每天一次，持续 4 或 7 天，总共 119 例）。根据脑组织血管紧张素 II 水平，另外一组在 12 小时后延迟给予低剂量坎地沙坦西酯治疗（14 例）。
再灌注后 4-12 小时，血管紧张素原 mRNA 增加，脑组织血管紧张素 II 水平短暂增加。坎地沙坦西酯治疗显著降低了接受高剂量治疗的大鼠的血压，中度降低了接受低剂量治疗的大鼠的血压。低剂量坎地沙坦西酯降低了梗死面积、脑水肿和神经功能缺损，而高剂量治疗则显示出有限的降低。此外，再灌注后的氧化应激随着低剂量治疗而降低。当脑组织血管紧张素 II 水平达到峰值后，再灌注后 12 小时以上仍存在治疗时间窗。
缺血后使用低剂量坎地沙坦西酯治疗可提供脑缺血损伤保护作用，并且可能具有临床相关的治疗时间窗。
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