Rho激酶抑制剂DL0805-0对大鼠离体胸主动脉的舒张作用及机制研究  

Vasorelaxant effect of Rho kinase inhibitor DL0805-0 on isolated rat aortic rings and its underlying mechanisms

作　　者：阎雨[1] 王夙博[1] 袁天翊[1] 焦晓臻 谢平 方莲花[1,2] 杜冠华 

机构地区：[1]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和新药筛选北京市重点实验室,北京100050 [2]中国医学科学院.北京协和医学院药物研究所天然药物活性物质与功能国家重点实验室,北京100050

出　　处：《中国药理学通报》2014年第4期473-477,共5页Chinese Pharmacological Bulletin

基　　金：国家科技部“重大新药创制”科技重大专项(No 2013ZX09103-001-008,2012ZX09103-101-078);国际科技合作专项项目(No 2011DFR31240)

摘　　要：目的探讨Rho激酶抑制剂DL0805-0对离体大鼠胸主动脉的舒张作用及作用机制。方法采用大鼠胸主动脉环张力测定法,观察DL0805-0对内皮完整或剔除的大鼠胸主动脉环的影响。应用法舒地尔、左旋硝基精氨酸甲醋(LNAME)、亚甲蓝、吲哚美辛、四乙胺(TEA)、格列本脲和4-氨基吡啶(4-AP)等工具药,研究DL0805-0舒张血管的作用机制。结果 DL0805-0能剂量依赖性的舒张KCl(60 mmol·L-1)和NE(0.1μmol·L-1)预收缩的大鼠胸主动脉环。LNAME可明显抑制DL0805-0对NE收缩血管的舒张作用,而亚甲蓝和吲哚美辛无明显影响。TEA可明显抑制DL0805-0对NE收缩血管的舒张作用,而格列本脲和4-AP无明显影响。DL0805-0能够明显抑制NE在无钙K-H液中引起的血管收缩和复钙诱导的外钙依赖性血管收缩。结论 DL0805-0具有明显的舒张血管作用,其作用可能依赖于血管内皮功能,另外开放血管平滑肌细胞上钙激活的钾离子通道以及阻滞钙离子通道可能也是作用机制之一。Aim To investigate the in vitro vasorelax-ant effect of DL0805-0, a Rho kinase inhibitor, on iso-lated rat thoracic aorta and explore its underlying mechanism. Methods Tension was measured to eval-uate the vasorelaxant effect of DL0805-0 on rat endo-thelium-intact and endothelium-denuded thoracic aorta rings. Rho kinase inhibitor fasudil, nitric oxide syn-thase inhibitor Nω-nitro-L-arginine methyl ester （ L-NAME）, guanylate cyclase inhibitor methylene blue, cyclooxygenase inhibitor indomethacin, calcium-activa-ted potassium channel blocker tetraethyl ammonium （ TEA ） , ATP-sensitive potassium channel blocker glibenclamide and voltage-dependent potassium chan-nel blocker 4-aminopyridine （ 4-AP ） were used to il-lustrate the mechanisms of vasorelaxant effect of DL0805-0 . Results DL0805-0 exerted vasorelaxation in a dose-dependent manner in KCl （60 mmol＆#183;L-1 ） or NE （ 0. 1 μmol ＆#183; L-1 ） -induced contraction.＆amp;nbsp;DL0805-0-induced vasorelaxation was significantly re-duced by L-NAME. However, methylene blue and in-domethacin did not significantly affect vasorelaxation of DL0805-0. In endothelium-denuded rings, TEA re-markably attenuated the vasorelaxant effect of DL0805-0 , while glibenclamide and 4-AP did not affect vasore laxation of DL0805-0 significantly. DL0805-0 also re-duced NE-induced transient contraction and inhibited contraction induced by increasing extracellular calci-um. Conclusion These results suggest that DL0805-0 induces vasorelaxation through an endothelium-depend-ent pathway. The opening of calcium-activated K＋channels and blocking of Ca2＋ channels in vascular smooth muscle cells may be one of the mechanisms of DL0805-0-induced vasorelaxation.

关 键 词：RHO 激酶 DL0805-0 大鼠胸主动脉环 内皮 钾通道 钙通道 DL0805-0 

分 类 号：R332[医药卫生—人体生理学] R322.121[医药卫生—基础医学]