Fasudil improves the endothelial dysfunction in the aorta of spontaneously hypertensive rats
Fasudil improves the endothelial dysfunction in the aorta of spontaneously hypertensive rats
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DOI：
10.1016/j.ejphar.2012.07.016
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发表时间：
2012-09-15
影响因子：
5
通讯作者：
Satoh, Keisuke
中科院分区：
文献类型：
--
作者：
Tsounapi, Panagiota;Saito, Motoaki;Satoh, Keisuke
我们研究了法舒地尔（Rho激酶抑制剂）对自发性高血压大鼠（SHRs）主动脉内皮功能障碍的影响。SHRs分为三组；腹腔注射（i.p）载药治疗SHRs (SHR)，法舒地尔3mg /kg i.p （Fas3）治疗SHRs，法舒地尔10mg /kg i.p （Fas10）治疗SHRs。以灌胃药Wistar大鼠为正常血压对照组。治疗6周后，采用尾袖法测量血压和心率。然后处死动物，用体外器官浴法观察主动脉的收缩舒张能力。观察Rho激酶活性、肌球蛋白轻链（MLC）、磷酸化MLC （phospho-MLC）、eNOS、phospho-eNOS蛋白表达及eNOS mRNA水平。与对照组相比，SHR表现出明显的过度收缩和松弛受损。法舒地尔10 mg/kg可明显纠正大鼠的过度收缩，恢复大鼠的舒张状态，显著降低动脉平均血压，而收缩压无明显变化。Rho激酶活性在SHR中显著升高，并被高剂量法舒地尔显著抑制。SHR中MLC和磷酸化-MLC蛋白水平略有上调。SHR中eNOS和磷酸化eNOS蛋白水平明显降低，法舒地尔治疗后这种异常明显正常化。eNOS基因表达差异无统计学意义。本研究表明，法舒地尔通过抑制Rho激酶活性，使eNOS的表达和磷酸化正常化，改善SHR模型中高血压引起的内皮功能障碍。(C) 2012 Elsevier B.V.版权所有
We investigated the effects of fasudil, a Rho kinase inhibitor, in the endothelial dysfunction of aortas from spontaneously hypertensive rats (SHRs). SHRs were divided in three groups; intraperitoneally (i.p.) vehicle-treated SHRs (SHR), SHRs treated with fasudil 3 mg/kg i.p. (Fas3), and SHRs treated with fasudil 10 mg/kg i.p. (Fas10). Vehicle-treated Wistar rats were used as normo-tensive control group. After a six-week-treatment, blood pressure and heart rate were measured by the tail cuff method. Afterwards animals were sacrificed and aortas were examined in vitro by organ bath studies to evaluate the contraction and relaxation ability. Rho kinase activity, myosin light chain (MLC), phosphorylated MLC (phospho-MLC), eNOS, phospho-eNOS protein expression and eNOS mRNA levels were evaluated. SHR demonstrated a significant hypercontractility and impaired relaxation compared to the control. Fasudil 10 mg/kg significantly corrected the hypercontractility, restored the relaxation, and significantly decreased the mean arterial blood pressure, while no change observed in the systolic blood pressure. Rho kinase activity was significantly higher in the SHR, and was significantly inhibited by the high dose of fasudil. There was a slight up-regulation in the MLC, and phospho-MLC protein levels in the SHR. eNOS and phospho-eNOS protein levels were significantly lower in the SHR, and this abnormality was significantly normalized by fasudil treatment. No significant difference was observed in the eNOS gene expression. This study suggests that fasudil by inhibiting the Rho kinase activity normalizes the eNOS expression and phosphorylation and ameliorates the endothelial dysfunction induced by hypertension in the SHR model. (C) 2012 Elsevier B.V. All rights reserved.