多沙唑嗪和美托洛尔对腹主动脉缩窄致高血压大鼠血管重塑的影响

Effect of doxazosin and metoprolol on vascular remodeling in rats with hypertension induced by abdominal aorta coarctation

目的观察多沙唑嗪及美托洛尔对腹主动脉缩窄(AAC)诱导的大鼠血管重塑的影响。方法采用AAC法成功建立血管重塑大鼠模型。2周后每天ig给予多沙唑嗪10 mg·kg-1或美托洛尔20 mg·kg-1,连续6周。采用颈总动脉插管测量大鼠的平均动脉压;采用HE染色和图像分析仪检测大鼠主动脉中膜厚度、中膜面积和中膜厚度与管腔内径比值;Masson染色检测纤维化;Western蛋白印迹法检测胶原蛋白和纤连蛋白表达。结果与假手术组血压(17.6±0.5)k Pa相比,模型组大鼠血压(23.3±0.7)k Pa显著升高(P<0.05),给予多沙唑嗪〔(20.5±0.7)k Pa〕或美托洛尔〔(19.0±0.4)k Pa〕均可有效降低血压(P<0.05)。HE染色结合图像分析仪分析发现,模型组大鼠血管中膜厚度、中膜面积及中膜厚度与血管内径比值较假手术组分别升高39.5%,46.4%和27.0%(P<0.05),给予多沙唑嗪或美托洛尔使血管的中膜厚度分别下降16.0%和26.1%(P<0.05),中膜面积分别下降22.8%和29.1%(P<0.05),中膜厚度与血管内径比值分别下降17.0%和26.0%(P<0.05)。Masson染色结果显示,与假手术组相比,模型组大鼠血管组织胶原蛋白的沉积增多,血管出现纤维化;而给予多沙唑嗪或美托洛尔可以缓解高血压诱导的纤维化发生。Western蛋白印迹结果显示,模型组大鼠血管组织中胶原蛋白和纤连蛋白的表达明显增加(P<0.05),而多沙唑嗪组和美托洛尔组较模型组胶原蛋白和纤连蛋白表达显著下降(P<0.05)。结论多沙唑嗪和美托洛尔可能通过抑制去甲肾上腺素与其特异性受体结合,从而选择性地阻断去甲肾上腺素对血管的诱导作用,逆转高血压诱导的血管重塑的发生。

OBJECTIVE To investigate the effect of doxazosin（DOX） and metoprolol（ MET） on vascular remodeling in rats with abdominal aorta coarctation （AAC）. METHODS An animal model was established by AAC. Two weeks later, the rats were treated with DOX （10 mg.kg-1 per day） or MET （20 mg.kg-1 per day） for six weeks. Blood pressure was measured using carotid artery intubation with a MP150 polygraph. The media thickness, wall cross-sectional area and thickness / internal diameter ratio were calculated by morphometry. Vascular fibrosis was evaluated by Masson′s trichrome staining. The collagen and fibronectin expression in vascules was measured by Western blotting. RESULTS Compared with the sham group 〔（17.6±0.5）kPa〕, the mean arterial blood pressure in the model group〔（23.3±0.7）kPa〕 was significantly increased（P〈0.05）, but was lowered by DOX 〔（20.5±0.7）kPa〕 and MET 〔（19.0±0.4） kPa〕 （P〈0.05）. Moreover, HE staining showed that tunica media thickness, artery vessel area and thickness / inner diameter in the model group were increased by 39.5%, 46.4% and 27.0%（P〈0.05）, respectively. The tunica media thickness was decreased by 16.0% and 26.1%（ P〈0.05）, respectively, the artery vessel area by 22.8% and 26.1%（P〈0.05）, respectively, and the thick-ness / inner diameter by 17.0% and 26.0%（ P〈0.05） when the rats were treated with DOX and MET. Masson staining showed that the collagen accumulation in vascules increased, suggesting that AAC induced fibrosis. Meanwhile, vascular fibrosis induced by AAC was also reduced by MET or DOX. Western blotting also proved that the increase of collagen and fibronectin induced by AAC could be attenuated by DOX and MET（P〈0.05）. CONCLUSION DOX and MET are effective in suppressing the role of norepi-nephrine in vassels, which can attenuate AAC-induced vassels remodeling by preventing the binding between norepinephrine and adrenoceptors.