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目的探讨内皮素-1受体拮抗剂对高脂血症家兔血管内皮功能的影响。方法 24只雄性新西兰大白兔随机分为对照组、模型组和BQ-123干预的内皮素-1拮抗剂组(拮抗剂组),每组8只。对照组饲喂普通饲料,模型组和拮抗剂组均饲喂高脂饲料,第6周时对照组和模型组兔静脉注射生理盐水4mL/d,连续5周,拮抗剂组静脉滴注选择性内皮素A受体拮抗剂BQ-123 4mL/d,30min滴完,连续5周。10周后检测3组血清总胆固醇、三酰甘油、高密度脂蛋白胆固醇和低密度脂蛋白胆固醇水平;采用免疫组织化学SP法检测兔主动脉组织内皮素-1和C反应蛋白(C-reactive protein,CRP)表达水平,采用PCR法检测兔主动脉组织CRP mRNA表达情况。结果拮抗剂组血清总胆固醇[(4.12±0.92)mmol/L]、三酰甘油[(1.43±0.58)mmol/L]、低密度脂蛋白胆固醇[(1.99±0.86)mmol/L]水平均低于模型组[(6.36±1.23)、(2.14±0.70)、(2.79±0.87)mmol/L](P<0.05),血清高密度脂蛋白胆固醇水平[(2.15±0.56)mmol/L]高于模型组[(1.02±0.42)mmol/L](P<0.05);模型组和拮抗剂组动脉粥样硬化病变相对面积(32.06%、12.35%)明显高于对照组(3.78%)(P<0.01),模型组高于拮抗剂组(P<0.05);拮抗剂组内膜厚度[(226.00±4.25)μm]、中膜厚度[(142.00±1.86)μm]、内膜面积[(0.34±0.04)μm2]、中膜面积[(0.46±0.04)μm2]均较模型组[(325.00±5.68)μm、(185.00±2.07)μm、(0.52±0.04)μm2、(0.73±0.05)μm2]明显下降(P<0.05),与对照组比较差异无统计学意义(P>0.05);拮抗剂组主动脉组织内皮素-1(1.39±0.78)、CRP mRNA(3.42±1.23)水平较模型组(3.98±0.76、6.37±1.66)明显下降(P<0.05);主动脉组织中内皮素-1与CRP mRNA表达水平呈正相关(r=0.346,P=0.024)。结论内皮素-1激活的内皮素A受体可导致家兔动脉粥样硬化斑块CRP表达上调,选择性内皮素A受体拮抗剂可预防家兔动脉粥样硬化进展。
Objective To investigate the effect of endothelin-1 receptor antagonist on vascular endothelial function in hyperlipidemic rabbits. Methods Twenty-four male New Zealand white rabbits were randomly divided into control group, model group and ET-1 antagonist group (antagonist group) interfered by BQ-123. The control group were fed normal diet, the model group and the antagonist group were fed with high-fat diet. The rabbits in the control group and the model group were intravenously injected with normal saline (4 mL / d) for 5 weeks. The antagonist group received intravenous drip selectivities Endothelin A receptor antagonist BQ-123 4mL / d, 30min drip finished for 5 weeks. The levels of serum total cholesterol, triglyceride, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol were measured after 10 weeks. The levels of endothelin-1 and C-reactive protein in the aorta of rabbits were detected by immunohistochemical SP method protein, CRP) were detected by RT-PCR. The expression of CRP mRNA in aortic tissue of rabbits was detected by PCR. Results The level of serum total cholesterol (4.12 ± 0.92 mmol / L), triglyceride (1.43 ± 0.58 mmol / L) and low density lipoprotein cholesterol (1.99 ± 0.86 mmol / L) The levels of serum high density lipoprotein cholesterol [(2.15 ± 0.56) mmol / L] in the model group were significantly higher than those in the model group [(6.36 ± 1.23) vs (2.79 ± 0.87) mmol / L (1.02 ± 0.42) mmol / L] in model group (P <0.05). The relative area of atherosclerosis (32.06%, 12.35%) in model group and antagonist group was significantly higher than that in control group (3.78% 0.01) in the model group and higher in the model group than in the antagonist group (P <0.05). In the antagonist group, the intima thickness [(226.00 ± 4.25) μm], the tunica media thickness [(142.00 ± 1.86) 0.0425μm2], and (0.46 ± 0.04) μm2] were significantly higher than those in the model group [(325.00 ± 5.68) μm, (185.00 ± 2.07) μm, (0.52 ± 0.04) μm2, (P <0.05), and there was no significant difference compared with the control group (P> 0.05). The levels of endothelin-1 (1.39 ± 0.78) and CRP mRNA (3.42 ± 1.23) 3.98 ± 0.76,6.37 ± 1.66) (P <0.05). There was a positive correlation between the expression of endothelin-1 and CRP mRNA in aorta (r = 0.346, P = 0.02 4). Conclusion Endothelin - 1 - activated endothelin - 1 receptor can induce the up - regulation of atherosclerotic plaque in rabbits. Selective endothelin - A receptor antagonist can prevent the development of atherosclerosis in rabbits.