血管紧张素1型受体拮抗剂对卒中易感型自发性高血压大鼠脑的保护作用

Preventive effect of AT1 receptor antagonist on the brain of spentaneously hypertensive stroske-prone rat

目的 研究长期口服血管紧张素 1受体拮抗剂氯沙坦对卒中易感型自发性高血压大鼠(SHRsp)的脑保护机制。 方法 6周龄雄性SHRsp 2 6只 ,随机分为生理盐水、小剂量氯沙坦 (10mg·kg 1·d 1)和大剂量氯沙坦 (30mg·kg 1·d 1) 3组 ,以 8只 6周龄雄性京都Wistar大鼠 (WKY)作为正常对照 ,记录体重、血压和脑卒中临床表现评分 ,18周后断头处死 ,光镜和电镜观察脑组织结构 ;TUNEL法检测神经细胞凋亡。 结果 18周后SHRsp大剂量用药组血压 (16 9 4± 10 1)mmHg明显低于未用药组 (2 2 5 5± 6 8)mmHg ,(P <0 0 5 ) ,小剂量用药组血压 (2 16 7± 8 3)mmHg ,与对照组比较改变不明显 (P >0 0 5 ) ;SHRsp未用药组脑卒中评分 (3 5± 0 6 )显著高于小剂量用药组 (0 7± 1 1)和大剂量用药组 (0 4± 0 7) ,(P <0 0 5 ) ;上述 3组神经元凋亡率分别为 :5 2 0± 16 7、14 0±4 4、13 9± 4 3,SHRsp未用药组神经元凋亡率高于小剂量和大剂量用药组 ,差异有显著性(P <0 0 5 )。 结论 氯沙坦能降低SHRsp脑卒中发生率、减少SHRsp神经细胞凋亡 ,此作用与血压无关。

Objective To investigate the preventive effects of AT1 receptor antagonist Lorsartan on blood pressure and stroke in spentaneously hypertensive stroske prone rat (SHRsp). Methods Twenty six 6 week aged SHRsp were divided into Losartan 30 mg/kg/d group (n=8), Losartan 10 mg/kg/d group (n=9) and normal saline group (n=9), and 8 sex and age matched Wistar Kyoto(WKY ) as control group (n=8). SHRsp were subjected to 1 5% saline solution as intake and administered 30 mg/kg/d Losartan or 10 mg/kg/d Losartan or equal volume of 0 9% saline solution for 18 weeks by gavage, respectively. The systolic blood pressure was measured by tail cuff sphygmomanometry and clinical score of stroke and survival time of SHRsp were recorded. The coronal brain sections was examined by microscope and electron microscope after decapitation. Apoptosis was analyzed by TdT mediated dUTP biotin nick end labeling and image analysis system. Results Losartan 10mg/kg/d showed no affect on systolic blood pressure but it prevented the occurrence of stroke. The clinical scores of stroke in Losartan 30 mg/kg/d group (0 4±0 7) and Losartan 10 mg/kg/d group (0 7±1 1) were both more decreased than in normal saline group(3 5±0 6) ( P <0 05, respectively). The number of cells exhibiting apoptosis in Losartan 30 mg/kg/d group, Losartan 10 mg/kg/d group and normal saline group were 13 9±4 3, 14 0±4 4, 52 0±16 7, respectively The neuron apoptosis in Losartan treatment groups was lower than that in the vehicle group ( P <0 05, respectively). Conclusions AngII has an effect on the pathophysiology of cerebrovascular lesion in saline drinking SHRsp. Chronic AT1 receptor antogonist therapy with Lorsartan markedly reduces both hypertension and end organ damage by preventing the development of cerebrovascular lesion and neuron apoptosis in SHRsp in the absence of a blood pressure fall.