新结构Rho激酶抑制剂对离体胸主动脉血管环舒张作用及机制研究

发布时间：2018-06-26 12:26

本文选题：Rho激酶抑制剂 + 离体血管环　；参考：《中国药理学通报》2016年10期

【摘要】：目的评价2个全新结构小分子Rho激酶抑制剂J35242和J35243对离体大鼠胸主动脉血管环的舒张作用,并探讨其作用机制。方法利用离体大鼠胸主动脉血管环模型,分别用高浓度KCl和去甲肾上腺素(norepinephrine,NE)预刺激,评价化合物的舒张血管活性;通过各种工具药干预,观察化合物舒张血管作用的内皮相关机制、钾通道相关机制和钙离子相关机制。结果 J35242和J35243可以剂量依赖性舒张高浓度KCl和NE预收缩的血管环,并呈现一定的内皮依赖性;L-NAME和亚甲蓝可在一定程度上影响其舒张作用;化合物还明显抑制由细胞内钙释放和外钙内流引起的血管收缩,说明其可能通过阻断钙离子通道发挥舒张血管作用;另外两个化合物可能不是通过开放钾离子通道发挥舒张血管作用。结论 J35242和J35243在体外具有一定的舒张血管作用,并且J35242的作用要强于J35243,其机制可能依赖于血管内皮功能,另外可能与抑制平滑肌细胞钙离子通道,降低细胞内钙离子浓度相关。
[Abstract]:Objective to evaluate the vasodilation effect of two novel small molecule Rho kinase inhibitors J35242 and J35243 on isolated rat thoracic aortic rings and to explore its mechanism. Methods the isolated rat models of thoracic aortic rings were prestimulated with high concentrations of KCl and norepinephrine (norepinephrineine NE) respectively to evaluate the vasodilation activity of the compounds. To observe the endothelium-related mechanism, potassium channel related mechanism and calcium ion related mechanism of vasodilation. Results J35242 and J35243 could dilate the precontracted rings of KCl and NE in a dose-dependent manner, and the endothelium-dependent L-NAME and methylene blue could influence the vasodilation to some extent. The compounds also significantly inhibited the vasoconstriction induced by intracellular calcium release and extracellular calcium influx, suggesting that the vasodilator may be mediated by blocking calcium channels. The other two compounds may not be vasodilating by opening potassium channels. Conclusion J35242 and J35243 have a certain vasodilation effect in vitro, and the effect of J35242 is stronger than that of J35243. The mechanism of J35242 may be dependent on vascular endothelial function, in addition, it may be related to the inhibition of calcium channel in smooth muscle cells and the decrease of intracellular calcium concentration.
【作者单位】：中国医学科学院北京协和医学院药物研究所药物靶点研究与新药筛选北京市重点实验室;山东大学国家糖工程技术研究中心;中国医学科学院北京协和医学院药物研究所活性物质发现与适药化研究北京市重点实验室;
【基金】：国家自然科学基金面上项目(No 81573645) 国家科技部“重大新药创制”科技重大专项(No 2013ZX09103001-008,2013ZX09508104,2013ZX09402203) 药物研究所基本业务费(No 2016CX09)
【分类号】：R965

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