liguzinediol基于肌浆网钙泵促进钙释放发挥正性肌力作用  

Liguzinediol exerts positive inotropic effect by enhancing Ca^(2+) release from sarcoplasmic reticulum mediated by sarcoplasmic reticulum Ca^(+)ATPase

作　　者：王伟[1] 李莎[1] 张梦丹[1] 高颖[1] 薛书银 陈可塑[2] 王中越 陈龙[1,3] 

机构地区：[1]南京中医药大学药学院国家科技部规范化中药药理实验室,江苏南京210046 [2]南京军区总医院干部病房呼吸科,江苏南京210002 [3]泰州中国医药城中医药研究院,江苏泰州225300

出　　处：《中国药理学与毒理学杂志》2016年第3期197-202,共6页Chinese Journal of Pharmacology and Toxicology

基　　金：江苏省自然科学基金(BK20131262);江苏省高校自然科学研究重大项目(14KJA360002)~~

摘　　要：目的研究liguzinediol(LZDO)正性肌力动力学特点及其作用机制。方法 1大鼠在体实验,经左侧颈外静脉缓慢推注LZDO 20 mg·kg-1,连续记录30 min左心室压力-容积环。2采用大鼠离体心脏,分别灌流咖啡因0.5 mmol·L-1以及咖啡因0.5 mmol·L-1+LZDO 100μmol·L-1,记录其左心室收缩力。3心肌细胞钙释放实验,分别灌流毒胡萝卜素2μmol·L-1以及毒胡萝卜素2μmol·L-1+LZDO 100μmol·L-1,记录其肌浆网钙释放。4采用灌流后的心脏,分离肌浆网膜蛋白之后,测定LZDO(1,10和100μmol·L-1)对肌浆网钙转运ATP酶(SERCA2a)活性作用。结果 1除心率及舒张末期容积外,LZDO 20 mg·kg-1显著减少收缩末期容积,显著增加收缩末期压力、每搏输出量、射血分数、心输出量、左室压力最大上升速率及搏出功(P<0.05)。2咖啡因0.5 mmol·L-1灌流5 min,大鼠离体心脏心率、左心室发展压及左心室内压最大上升速率增加,灌流30 min后各指标均降低。而LZDO 100μmol·L-1则能对抗咖啡因0.5 mmol·L-130 min的这种降低作用(P<0.05)。3毒胡萝卜素2μmol·L-1显著降低心肌细胞钙释放,从标准化的正常灌流液组(100±5)%降低到(51±5)%(P<0.05),而LZDO 100μmol·L-1未能对抗毒胡萝卜素的作用〔(49±4)%〕。4 LZDO(10和100μmol·L-1)显著增加心肌肌浆网钙泵活性,从正常灌流液组0.98±0.10分别增加到1.17±0.20及(1.43±0.09)μmol Pi·g-1·h-1,呈现浓度依赖性(r=0.85,P<0.05)。结论 LZDO通过增加钙泵活性提高肌浆网钙浓度梯度,从而间接增加钙释放而发挥正性肌力作用。基于其作用机制,LZDO有可能被开发为临床上使用的正性肌力药物。OBJECTIVE To explore kinetic features and its underlying mechanism of the positive inotropic effect of liguzinediol（LZDO）in rats. METHODS ① An In vivo study was made to record the effect of LZDO 20 mg·kg^-1injected for 30 consecutive min from the left external jugular vein on pressurevolume relationships. ② Ex vivo study was used to record the antagonistic effect of LZDO on reduced contractility induced by caffeine. Caffeine and LZDO were perfused as fol ows：normal perfusion solution,caffeine 0.5 mmol·L^- 1,and then caffeine 0.5 mmol·L^- 1＋LZDO 100 μmol·L- 1. ③ Ca^2 ＋transient from cardiomyocyte sarcoplasmic reticulum（SR）was measured to analyze the effect of LZDO on Ca^2 ＋release blocked by thapsigargin. Thapsigargin and LZDO were perfused as follows： normal perfusion solution,thapsigargin 2 μmol·L^- 1,and then thapsigargin 2 μmol·L^- 1＋LZDO 100 μmol·L^- 1.④ The SR vesicles were prepared and the effect of LZDO（1,10 and 100 μmol·L^-1）on sarcoplasmic reticulum Ca^2＋ATPase（SERCA2a）activity was determined according to the ultramicro-Ca2＋-ATP enzyme kit. RESULTS ① LZDO 20 mg · kg^- 1significantly reduced the end- systolic volume（Ves） and enhanced the end- systolic pressure（Pes）,stroke volume（SV）,ejection fraction（EF）,cardiac output（CO）,peak rate of rise of left ventricular pressure（＋dp/dtmax）and stroke work（SW）（P〈0.05）.However,LZDO 20 mg·kg^-1did not significantly change the heart rate（HR）or the end-diastolic volume（Ved）. ② Caffeine 0.5 mmol · L^- 1significantly enhanced HR,left ventricular developed pressure（LVDP）,and ＋dp∶dtmaxat 5 min after caffeine and decreased at 30 min. However,LZDO 100 μmol·L-1restored the reduced HR,LVDP,and ＋dp/dtmaxinduced by caffeine at 30 min（P〈0.05）. ③Thapsigargin2 μmol·L^-1significantly reduced the SR Ca^2＋transient from perfusion solution group（100±5）% to（51±5）%（P〈0.05）and LZDO 100 μmol · L^- 1failed to restore the decreased Ca^2 ＋transient�

关 键 词：LIGUZINEDIOL 钙释放 强心药 肌浆网钙转运ATP酶类 

分 类 号：R96[医药卫生—药理学]