Protective effect of candesartan in experimental ischemic stroke in the rat mediated by AT2 and AT4 receptors
Protective effect of candesartan in experimental ischemic stroke in the rat mediated by AT2 and AT4 receptors
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DOI：
10.1097/hjh.0b013e32830dd5ee
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发表时间：
2008-10-01
影响因子：
4.9
通讯作者：
Achard, Jean-Michel
中科院分区：
文献类型：
--
作者：
Faure, Sebastien;Bureau, Annabelle;Achard, Jean-Michel
目的 探讨AT(2)和AT(4)血管紧张素受体对AT(1)受体阻滞剂坎地沙坦对急性缺血性脑卒中保护作用的贡献。方法通过在Sprague-Dawley大鼠右侧颈内动脉注射校准微球(50μm)诱发栓塞性脑卒中。结果赖诺普利预处理24 h可显着抑制内源性血管紧张素的产生。死亡率和梗塞体积增加，而坎地沙坦 24 小时可降低血压至相同程度，但没有有害作用。使用坎地沙坦进行更持续的预处理 5 天可显着降低死亡率、神经功能缺损和梗塞面积。 AT(2)受体拮抗剂PD123319和AT(4)受体拮抗剂divalinal消除了5天AT(1)阻断的保护作用。坎地沙坦预处理大鼠中联合阻断 AT(2) 和 AT(4) 导致死亡率、神经功能缺损和梗塞体积增加，其程度与赖诺普利预处理相似。术前24小时同时服用赖诺普利完全削弱了坎地沙坦预处理的保护作用。给予外源性血管紧张素IV (1 nmol)可逆转赖诺普利预处理的有害作用。结论 AT(1)阻断5天引起的急性脑缺血的保护作用与血压无关，并且由AT(2)和AT(4)血管紧张素受体介导。
Objectives The contribution of the AT(2) and AT(4) angiotensin receptors to the protective role of the AT(1) receptor blocker candesartan in acute ischemic stroke was investigated.Methods Embolic stroke was induced by injection of calibrated microspheres (50 mu m) in the right internal carotid in Sprague-Dawley rats.Results Inhibition of production of endogenous angiotensins by pretreatment for 24 h with lisinopril significantly increased mortality and infarct volume, whereas candesartan for 24 h reduced blood pressure to the same extent but had no deleterious effect. A more sustained pretreatment with candesartan for 5 days significantly decreased mortality, neurological deficit and infarct size. The AT(2) receptor antagonist PD123319 and the AT(4) receptor antagonist divalinal abolished the protective effect of 5 days' AT(1) blockade. Combined blockade of AT(2) and AT(4) in candesartan pretreated rats resulted in an increased mortality, neurological deficit and infarct volume of similar magnitude to lisinopril pretreatment. Coadministration of lisinopril 24 h before surgery completely blunted the protective effect of candesartan pretreatment. Administration of exogenous angiotensin IV (1 nmol) reversed the deleterious effect of lisinopril pretreatment.Conclusion Protection against acute cerebral ischemia induced by AT(1) blockade for 5 days is blood pressure independent and mediated by both AT(2) and AT(4) angiotensin receptors.