The Effect of First-in-Class Small Molecule RhoA Inhibitor, HL07, on the Phenylephrine-induced Artery Contraction
文献类型：期刊论文
| 作者 | Zhang, Yan1; Deng, Jing3; Ma, Sheng1; Xue, Lin1; Zhu, Jin3; Zhu, Wei-liang2 ; Jiang, Hua-liang2,3; Li, Jian3; Miao, Li-yan1
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| 刊名 | CURRENT PHARMACEUTICAL DESIGN
 |
| 出版日期 | 2012-09 |
| 卷号 | 18期号:27页码:4258-4264 |
| 关键词 | RhoA/Rho-kinase pathway HL07 RhoA activation vasodilation binding affinities |
| ISSN号 | 1381-6128 |
| DOI | 10.2174/138161212802430387 |
| 文献子类 | Review |
| 英文摘要 | The RhoA/ROCK inhibitors have emerged as a new promising treatment for cardiovascular diseases. Recently, we first reported a series of first-in-class small molecular RhoA inhibitors and a chemical compound named HL07 showed high RhoA inhibition activities. In this study, we aimed to explore the pharmacological effect and possible mechanism of HL07 on agonists-induced vasoconstriction. Results showed that 1) in rat thoracic aorta (TA) rings, HL07(0 similar to 180 mu mol/L) effectively inhibited phenylephrine (PE)-induced contraction in concentration-dependent manner, whereas the half maximal inhibitory concentration (IC50) being 156.93 mu mol/L, while it produced weak inhibition on high-K+ -induced contraction. Furthermore, in the presence of nifedipine and thapsigargin (Nif/TSG), HL07 had a comparable degree of inhibition on PE-induced contraction with IC50=149.52 mu mol/L; especially at the concentration (0 similar to 150 mu mol/L), the inhibition was greater than the inhibition in absence of Nif/TSG (P<0.01). In addition, HL07 displayed greater inhibition on pulmonary artery (PA) rings (IC50=134.97 mu mol/L) than on TA rings. 2) HL07 potently blocked RhoA activation stimulated by PE in concentration-dependent manner in human cerebrovascular smooth muscle cells (HBVSMCs), when HL07 at 10, 2, 0.25 mu mol/L, the corresponding inhibition rates were 64 +/- 5%, 42 +/- 7%, 31 +/- 5%, respectively; and at the same concentrations, HL07 had no significant effect on RhoA mRNA level. 3) In HBVSMCs, RhoA activity was increased by pre-incubating with GNP, but HL07 showed inhibitory effect on this tendency. These results indicate that HL07 produces significant inhibitory effects on PE-induced vascular smooth muscle contraction. The inhibitory effects of HL07 were mainly contributed to its inhibition on RhoA/Rho-kinase pathway through blocking RhoA activation, and the binding affinities of HL07 for RhoA preference over the GNP might be responsible for the inhibition of HL07 on RhoA activity. |
| WOS关键词 | INDUCED CA2+ SENSITIZATION ; C3 EXOENZYME ; KINASE ; PULMONARY ; RAT ; Y-27632 |
| 资助项目 | National Natural Science Foundation of China[21002028] ; National Natural Science Foundation of China[20902022] ; National S&T Major Project, China[2011ZX09102-005-02] ; Natural Science Foundation of Jiangsu Province[BK2008172] ; Shanghai Committee of Science and Technology[11DZ2260600] ; Fundamental Research Funds for the Central Universities[00000000] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000307871200018 |
| 出版者 | BENTHAM SCIENCE PUBL LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277977]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Miao, Li-yan |
| 作者单位 | 1.Soochow Univ, Affiliated Hosp 1, Dept Clin Pharmacol Res Lab, Suzhou 215006, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China 3.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zhang, Yan,Deng, Jing,Ma, Sheng,et al. The Effect of First-in-Class Small Molecule RhoA Inhibitor, HL07, on the Phenylephrine-induced Artery Contraction[J]. CURRENT PHARMACEUTICAL DESIGN,2012,18(27):4258-4264. |
| APA | Zhang, Yan.,Deng, Jing.,Ma, Sheng.,Xue, Lin.,Zhu, Jin.,...&Miao, Li-yan.(2012).The Effect of First-in-Class Small Molecule RhoA Inhibitor, HL07, on the Phenylephrine-induced Artery Contraction.CURRENT PHARMACEUTICAL DESIGN,18(27),4258-4264. |
| MLA | Zhang, Yan,et al."The Effect of First-in-Class Small Molecule RhoA Inhibitor, HL07, on the Phenylephrine-induced Artery Contraction".CURRENT PHARMACEUTICAL DESIGN 18.27(2012):4258-4264. |
入库方式： OAI收割
来源：上海药物研究所
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