异长春花苷内酰胺注射给药对心血管系统影响的实验研究  

Experimental Research on Effect of Strictosamide Injection on Cardiovascular System

作　　者：苏真真[1,2] 李娜[1,2] 曹亮[1,2] 孟兆青[1,2,3] 刘文君[1,2,3] 丁岗[1,2,3] 王振中[1,2,3] 萧伟[1,2,3] 

机构地区：[1]江苏中康药物科技有限公司,南京210017 [2]江苏康缘药业股份有限公司,连云港222000 [3]中药制药过程新技术国家重点实验室,连云港222000

出　　处：《世界科学技术-中医药现代化》2014年第7期1558-1564,共7页Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology

基　　金：科学技术部国家重大新药创制项目(2009ZX09103-379):候选药物-异长春花苷内酰胺的研究;负责人:丁岗;江苏省科学技术厅科技支撑-社会发展项目(BE2009618):围绕中药胆木开展一;四类创新新药的临床前研究;负责人:丁岗

摘　　要：目的:观察异长春花苷内酰胺大剂量注射给药对麻醉Beagle犬心血管系统的影响,并考察其体外对离子通道的抑制作用。方法:采用生理记录仪观察异长春花苷内酰胺静脉注射前后不同时间点Beagle犬收缩压(Sys),舒张压(Dia),平均动脉压(MBP),心率(HR),心电图PR间期、QRS间期、QT间期、QTcb间期、QTcv间期等指标的变化;应用全细胞膜片钳技术考察不同浓度异长春花苷内酰胺对CHOhERG细胞上hERG钾离子通道和HEK-293-Nav1.5细胞上Nav1.5钠离子通道的抑制作用。结果:与空白对照组相比,异长春花苷内酰胺60、18 mg·kg-1剂量组、溶媒对照组(含吐温-80)于给药后15 min Sys、Dia、MBP、HR明显降低(P<0.05),给药结束后各项指标可见恢复。与溶媒对照组相比,各给药剂量组在各观测时间点无显著性差异。与空白对照组及自身给药前相比,60、18、6 mg·kg-1剂量组、溶媒对照组于给药后15 min QT、QTcb、QTcv间期明显延长(P<0.05),给药结束后可见一定程度的恢复。与溶媒对照组相比,各给药剂量组QT、QTcb和QTcv间期在各观测时间点无显著性差异。异长春花苷内酰胺对hERG钾离子通道和Nav1.5离子通道抑制作用较弱,IC50为560.8μmol·L-1及>900μmol·L-1,远远大于阳性对照药。结论:异长春花苷内酰胺大剂量单次静脉注射对Beagle犬可能有一定的降低血压、减慢心率及延长QT间期的作用,停药后可恢复。其中血压降低、心率减慢与溶媒中所含吐温-80有关。体外对hERG钾离子通道和Nav1.5离子通道无明显影响,提示异长春花苷内酰胺对动物QT间期的影响可能为其它作用机制所致。This study was aimed to investigate the effects of high-dose strictosamide injection on cardiovascular system of anesthetized beagle dogs and to examine the inhibition of strictosamide on ion channels in vitro. Indexes such as changes of systolic blood pressure （Sys）, diastolic blood pressure （Dia）, mean blood pressure （MBP）, heart rate （HR）, PR, QRS, QT, QTcb and QTcv at different time points before and after strictosamide injection in dogs were monitored by the polygraph system. The inhibition of strictosamide at different concentrations on hERG potassium channel in CHO-hERG cells and Nav1.5 sodium channel in HEK-293-Nav1.5 cells were measured by whole-cell patch-clamp method. The results showed that compared with the blank control group, Sys, Dia, MBP and HR were obviously declined 15 min after medication in the strictosamide （60, 18 mg·kg-1） group and the vehicle-control group （containing tween-80） （P〈0.05）. After medication, all indexes were recovered. Compared to the vehicle-control group, there were no significant differences at different time points in each medication groups. Compared with the blank control group and before medication, the QT interval, QTcb and QTcv were significantly prolonged 15 min after medication in the strictosamide （60, 18, 6 mg·kg-1） group and the vehicle-control group （P〈 0.05）. When medication stopped, indexes were recovered at certain level. Compared with the vehicle-control group, there were no sig-nificant differences of QT interval, QTcb and QTcv of each medication group at different time points （P〉 0.05）. The inhibition of strictosamide on hERG potassium channel and Nav1.5 sodium channel were weak with IC50 values of 560.8 μM and 〉 900 μM, respectively, which were far greater than the positive controls. It was concluded that single, high-dose intravenous injection of strictosamide may lead to a lower blood pressure, a slower heart rate and a prolongation on the QT interval in beagle dogs, which returned to basal levels whe

关 键 词：异长春花苷内酰胺 血压 心电图 HERG NAV1.5 

分 类 号：R285.5[医药卫生—中药学]