Vasodilatory Effect of a Novel Rho-Kinase Inhibitor, DL0805-2, on the rat Mesenteric Artery and its Potential Mechanisms
Vasodilatory Effect of a Novel Rho-Kinase Inhibitor, DL0805-2, on the rat Mesenteric Artery and its Potential Mechanisms
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新型Rho激酶抑制剂DL0805-2对大鼠肠系膜动脉的舒血管作用及其潜在机制
DOI：
10.1007/s10557-014-6544-7
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发表时间：
2014-08
影响因子：
3.4
通讯作者：
Guan-Hua Du(*)
中科院分区：
文献类型：
--
作者：
Tian-Yi Yuan;Yu Yan;Yu-Jie Wu;Xiao-Na Xu;Li Li;Xiao-Zhen Jiao;Ping Xie;Lian-Hua Fang(*);Guan-Hua Du(*)
目的：在本研究中，我们研究了一种新型支架rho激酶抑制剂DL0805-2对大鼠离体动脉环（包括肠系膜、腹侧尾动脉和肾动脉）的血管扩张作用。我们还利用肠系膜动脉环研究了其血管扩张作用的潜在机制。方法采用DMT多丝肌图系统检测离体小动脉张力。使用了几种药物来验证潜在的机制。结果dl0805 -2（10−7-10−4M）抑制KCl （60 mM）诱导的3种小动脉环血管收缩（肠系膜、肾和腹侧尾动脉环的pEC50分别为5.84±0.03、5.39±0.03和5.67±0.02）。预先用DL0805-2（1、3或10 μM）减毒KCl （10 - 60 mM）和血管紧张素II （AngII; 10−6M）诱导肠系膜动脉环血管收缩。对大鼠肠系膜动脉的舒张作用部分依赖于内皮（pEC50：完整内皮组为6.02±0.05，剥离内皮组为5.72±0.06）。DL0805-2抑制Ca2+的内流和释放。此外，DL0805-2可阻断AngII诱导的肌球蛋白轻链（MLC）和肌球蛋白结合亚基肌球蛋白磷酸酶（MYPT1）磷酸化水平的升高。DL0805-2对K+通道影响不大。结论DL0805-2对离体大鼠小动脉具有血管舒张作用，可能通过内皮、Ca2+通道和Rho/ROCK通路发挥作用。
PurposeIn the present study, we investigated the vasodilatory effect of a novel scaffold Rho-kinase inhibitor, DL0805-2, on isolated rat arterial rings including mesenteric, ventral tail, and renal arteries. We also examined the potential mechanisms of its vasodilatory action using mesenteric artery rings.MethodsA DMT multiwire myograph system was used to test the tension of isolated small arteries. Several drugs were employed to verify the underlying mechanisms.ResultsDL0805-2 (10−7–10−4M) inhibited KCl (60 mM)-induced vasoconstriction in three types of small artery rings (pEC50: 5.84 ± 0.03, 5.39 ± 0.03, and 5.67 ± 0.02 for mesenteric, renal, and ventral tail artery rings, respectively). Pre-incubation with DL0805-2 (1, 3, or 10 μM) attenuated KCl (10–60 mM) and angiotensin II (AngII; 10−6M)-induced vasoconstriction in mesenteric artery rings. The relaxant effect on the rat mesenteric artery was partially endothelium-dependent (pEC50: 6.02 ± 0.05 for endothelium-intact and 5.72 ± 0.06 for endothelium-denuded). The influx and release of Ca2+were inhibited by DL0805-2. In addition, the increased phosphorylation levels of myosin light chain (MLC) and myosin-binding subunit of myosin phosphatase (MYPT1) induced by AngII were blocked by DL0805-2. However, DL0805-2 had little effect on K+channels.ConclusionsThe present results demonstrate that DL0805-2 has a vasorelaxant effect on isolated rat small arteries and may exert its action through the endothelium, Ca2+channels, and the Rho/ROCK pathway.
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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
发表时间：
2012-05-18
期刊：
Molecules (Basel, Switzerland)
影响因子：
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作者：
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影响因子：
64.8
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通讯作者：
Narumiya, S