摘要
目的探讨新型降压药阿奇沙坦酯(azilsartan medoxomil,TAK-491)能否抑制球囊损伤后血管内膜增生及其可能机制。方法选取清洁级雄性200~250g SD大鼠48只,随机分为4组,即假手术组、模型组、阿奇沙坦酯低剂量组、阿奇沙坦酯高剂量组,每组12只。建立模型后,阿奇沙坦酯低剂量组与高剂量组SD大鼠分别按2mg/kg和4mg/kg每天给予3ml药物灌胃,模型组和假手术组大鼠每天用3ml生理盐水灌胃。于术后14、28天取大鼠颈总动脉行HE染色,观察血管形态学变化,同时计算内膜面积(IA)、中膜面积(MA)及内膜/中膜面积比(IA/MA)。免疫组化技术测量增殖细胞核抗原(PCNA)、Toll样受体4(TLR4)、核因子-κB(NF-κB)p65表达变化结果,酶联免疫吸附测定(ELISA)血清中肿瘤坏死因子-α(TNF-α)及白细胞介素-6(IL-6)水平。结果与模型组对比发现,药物低、高剂量组术后14、28天IA、IA/MA明显减少(P<0.05),颈总动脉的PCNA、TLR4、NF-κB p65蛋白的表达明显降低(P<0.05),血清中TNF-α、IL-6表达明显降低(P<0.05)。与假手术组进行对比发现,手术组术后14、28天IA、IA/MA明显增加(P<0.05),颈总动脉的PCNA、TLR4、NF-κB p65的表达明显增加(P<0.05),血浆中TNF-α、IL-6表达明显增加(P<0.05)。结论阿奇沙坦酯可以减轻损伤后血管再狭窄发生率,其作用机制可能是通过抑制TLR4介导的NF-κB通路,减少了下游炎性相关因子TNF-α、IL-6等的表达,继而减少内膜增生而实现的。
Objective To investigate the inhibitory effect of a new antihypertensive drug on carotid artery intimal hyperplasia in balloon-injured rats and its possible mechanism.Methods A total of 48 SD rats were randomly divided as follows:sham operation group,model group,low-dose Azilsartan medoxomil group and high-dose Azilsartan medoxomil group(n=12). The rats in sham operateion group and model group were treated by by gavage with 3ml normal saline every day,and rats in low-dose Azilsartan medoxomil group and high-dose Azilsartan medoxomil group were treated by by gavage at adose of 2mg/kg and 4mg/kg Azilsartan medoxomil(3ml)every day.14 and 28 days after operation,we can observe the morphological changes of the injured arteries by HE staining and measure intimal area(IA),medial area(MA),the intimal/medial area ratio(IA/MA).The expression of PCNA,TLR4,NF-κB p65 in each group were detected by immunohistochemistry and the plasma level of TNF-α,IL-6 were detected by enzyme-linked immunosorbent assay(ELISA).Results Compared with the model group,the intimal area and the intimal/medial area ratio were significantly reduced in the low-dose group and hige-dose group (P〈0.05). The expression of PCNA, TLR4 and NF-κB p65 in carotid artery were significantly lower (P〈0.05). The plasma level of TNF-α、IL-6 were significantly lower (P〈0.05). Compared with the sham operation group, the intimal area and the intimal/medial area ratio were significantly increased in the operation group (P〈0.05)and the expression of PCNA, TLR4 and NF-κB p65 in carotid artery were significantly increased (P〈0.05). The plasma level of TNF-α、IL-6 were significantly increased (P〈0.05).Conclusion Azilsartan medoxomil can alleviate the incidence of vascular restenosis.The mechanism of action possibly was related to reducing the expression of inflammatory factors such as TNF-α,IL-6 by TLR4/NF-κB pathway and inhibiting the carotid artery intimal hyperplasia.
出处
《医学研究杂志》
2017年第11期111-115,共5页
Journal of Medical Research
关键词
阿奇沙坦酯
球囊损伤
内膜增生
Azilsartan medoxomil Balloon injury Intimal hyperplasia