Therapeutic effects of postischemic treatment with hypotensive doses of an angiotensin II receptor blocker on transient focal cerebral ischemia
Therapeutic effects of postischemic treatment with hypotensive doses of an angiotensin II receptor blocker on transient focal cerebral ischemia
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DOI：
10.1097/hjh.0b013e32834bbb30
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发表时间：
2011-11-01
影响因子：
4.9
通讯作者：
Kohno, Masakazu
中科院分区：
文献类型：
--
作者：
Fu, Hua;Hosomi, Naohisa;Kohno, Masakazu
背景 缺血后低血压剂量的坎地沙坦对脑缺血的神经血管保护作用并不一致。本研究的目的是确定再灌注后脑血管紧张素II的水平以及降压剂量坎地沙坦治疗脑缺血的疗效和治疗时间窗。 方法在氟烷麻醉下，采用线法对SD大鼠进行右侧大脑中动脉闭塞（60分钟）再灌注。再灌注后评估脑血管紧张素 II 的蛋白质水平和肾素-血管紧张素系统成分的 mRNA 水平（总共 n = 184）。再灌注后立即口服低剂量或高剂量坎地沙坦西酯（分别为每天 1 或 10 mg/kg），每天一次，持续 4 或 7 天（总共 n = 119）。另一组根据脑血管紧张素 II 水平延迟 12 小时后接受低剂量坎地沙坦酯治疗 (n = 14)。 结果 再灌注后 4-12 小时，脑血管紧张素 II 水平短暂升高，随后血管紧张素原 mRNA 增加。坎地沙坦西酯治疗显着降低了高剂量大鼠的血压（BP），而接受低剂量的大鼠则中度降低了血压（BP）。低剂量的坎地沙坦西酯可减少梗塞面积、脑水肿和神经功能缺损，而高剂量治疗的减少效果有限。此外，低剂量治疗可减少再灌注后的氧化应激。治疗时间窗在再灌注后至少12小时开放，此时脑血管紧张素II水平达到峰值。结论使用低降压剂量的坎地沙坦西酯进行缺血后治疗可提供针对脑缺血损伤的保护作用，并且可能具有临床相关的治疗时间窗。 J Hypertens 29: 2210-2219 (C) 2011 Wolters Kluwer Health 垂直条 Lippincott Williams & Wilkins。
Background 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.Method 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).Results 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.Conclusion Postischemic treatments using low hypotensive doses of candesartan cilexetil provided protection against cerebral ischemic injury and may have a clinically relevant therapeutic time window. J Hypertens 29: 2210-2219 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.