新型AT1受体拮抗剂--化合物EXP-2528对大鼠局灶性脑缺血再灌注损伤的保护作用  

Protective Effect of Compound EXP-2528 on Brain Ischemia-Reperfusion Injury in Rats

作　　者：刘慧青[1] 魏欣冰[1] 张斌[1] 陈琳[1] 孙霞[1] 王建武[2] 张岫美[1] 

机构地区：[1]山东大学医学院药理学研究所,济南250012 [2]山东大学化学与化工学院,济南250012

出　　处：《中国药学杂志》2008年第4期276-279,共4页Chinese Pharmaceutical Journal

基　　金：国家自然科学基金资助项目(30572187);山东省自然基金青年基金项目(Q2004C05)

摘　　要：目的研究新型AT1受体拮抗剂——化合物EXP-2528对大鼠局灶性脑缺血再灌注损伤的保护作用及探讨初步机制,为其发展成治疗缺血性脑血管病的自主产权的创新药物奠定基础。方法健康雄性Wistar大鼠,随机分为假手术组;缺血再灌注组;氯沙坦5mg·kg-1·d-1组;化合物EXP-25282.5,5mg·kg-1·d-1组。利用大脑中动脉栓线阻断法造成大鼠局灶性脑缺血再灌注损伤模型,通过神经功能评分、TTC染色测定梗死体积观察化合物EXP-2528对大鼠局灶性脑缺血再灌注损伤的保护作用。同时以放射免疫法测定血浆血管紧张素Ⅱ(AngⅡ)和内皮素(ET)的水平,探讨其初步机制。结果大鼠局灶性脑缺血2h再灌注24h后,出现明显的神经功能缺损体征,脑梗死体积明显增大;血浆AngⅡ和ET的水平明显升高。氯沙坦及化合物EXP-2528均可明显改善脑缺血再灌注大鼠的神经功能障碍,缩小脑梗死体积;降低脑缺血再灌注损伤所致血浆ET水平的升高,而进一步升高血浆AngⅡ的水平。结论预先给予新型AT1受体拮抗剂EXP-2528同氯沙坦一样对大鼠局灶性脑缺血再灌注损伤有明显保护作用。OBJECTIVE To investigate the protective effect and preliminary mechanism of compound EXP-2528, a novel AT1 receptor antagonist, on focal brain ischemia-reperfusion injury in rats. METHODS Focal cerebral ischemia was induced by the middle cerebral artery occlusion （MCAO） for 2 h followed by 24 h reperfusion. Either selective ATⅡ antagonists losartan （5mg·kg^-1·d^-1） or compound EXP-2528 （2. 5 or 5 mg·kg^-1·d^-1） , was given intragastrically over a 14 d period before the induction of ischemia. 24 h after reperfusion, the behavioral tests, the infarct volume by 2,3,5-triphenyltetrazofium chloride （ TTC ） staining were used to evalu- ate the damage to central nervous system. The plasma angiotensin Ⅱ （Ang Ⅱ） and endothelin （ET） levels were determined by radio- immunoassay. RESULTS Neurological deficit scores and the percentage of infarction in ipsilateral hemisphere were reduced significantly by pretreatment with losartan （5 mg·kg^-1·d^-1）, or compound EXP-2528 （2.5,5mg·kg^-1·d^-1） comparing with ischemi- a-reperfusion group. The plasma Ang Ⅱ and ET level were increased markedly after focal cerebral ischemia-reperfusion injury, the endothelin level was deceased by pretreatment with losartan or different doses of compound EXP-2528, but Ang Ⅱ level was increased. CONCLUSION Novel AT1 receptor antagonist compound of EXP-2528, as same as losartan, efficiently protected brain injury from focal cerebral ischemia/reperfusion in rats.

关 键 词：脑缺血再灌注损伤 血管紧张素Ⅱ 内皮素 AT1受体拮抗剂 化合物EXP-2528 

分 类 号：R965[医药卫生—药理学]