The vasorelaxant mechanisms of a Rho kinase inhibitor DL0805 in rat thoracic aorta.
The vasorelaxant mechanisms of a Rho kinase inhibitor DL0805 in rat thoracic aorta.
复制标题
Rho激酶抑制剂DL0805在大鼠胸主动脉中的血管舒张机制。
DOI：
10.3390/molecules17055935
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发表时间：
2012-05-18
期刊：
影响因子：
--
通讯作者：
Du G
中科院分区：
文献类型：
--
作者：
Gong L;Peng J;Fang L;Xie P;Si K;Jiao X;Wang L;Du G
Rho激酶已被认为是治疗心血管疾病的潜在靶点。Rho-激酶信号传导途径实质上参与血管收缩。本研究旨在观察Rho激酶抑制剂DL 0805对离体大鼠主动脉环的舒张作用，并探讨其可能的作用机制。结果发现，DL 0805以剂量依赖性方式对NE或KCl诱导的去内皮环的持续收缩和部分舒张功能丧失产生舒张作用。一氧化氮合酶抑制剂Nω-硝基-L-精氨酸甲酯、鸟苷酸环化酶抑制剂亚甲蓝和环氧合酶抑制剂吲哚美辛可显著降低DL 0805诱导的血管舒张作用。电压依赖性K+通道阻断剂4-氨基吡啶显著减弱DL 0805诱导的舒张作用。然而，ATP敏感性K+通道阻断剂格列本脲和钙激活的K+通道阻断剂四乙铵不影响DL 0805诱导的舒张。在内皮剥脱的血管环中，DL 0805还减少NE诱导的短暂收缩，并抑制由增加外部钙引起的收缩。这些结果表明，DL 0805是一种新的血管舒张化合物与抑制Rho/ROCK信号通路。NO-cGMP通路可能参与DL 0805舒张内皮完整主动脉的作用。DL 0805的血管舒张作用部分通过开放电压依赖性K+通道介导。
Rho-kinase has been suggested as a potential therapeutic target in the treatment of cardiovascular diseases. The Rho-kinase signaling pathway is substantially involved in vascular contraction. The aim of the present study was to evaluate the vasorelaxant effects of Rho kinase inhibitor DL0805 in isolated rat aortic rings and to investigate its possible mechanism(s). It was found that DL0805 exerted vasorelaxation in a dose-dependent manner in NE or KCl-induced sustained contraction and partial loss of the vasorelaxation under endothelium-denuded rings. The DL0805-induced vasorelaxation was significantly reduced by the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester, the guanylate cyclase inhibitor methylene blue and the cyclooxygenase inhibitor indomethacin. The voltage-dependent K+ channel blocker 4-aminopyridine remarkably attenuated DL0805-induced relaxations. However, the ATP-sensitive K+ channel blocker glibenclamide and Ca2+-activated K+ channel blocker tetraethylammonium did not affect the DL0805-induced relaxation. In the endothelium-denuded rings, DL0805 also reduced NE-induced transient contraction and inhibited contraction induced by increasing external calcium. These findings suggested that DL0805 is a novel vasorelaxant compound associated with inhibition of Rho/ROCK signaling pathway. The NO-cGMP pathway may be involved in the relaxation of DL0805 in endothelium-intact aorta. The vasorelaxant effect of DL0805 is partially mediated by the opening of the voltage-dependent K+ channels.
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