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liguzinediol基于肌浆网钙泵促进钙释放发挥正性肌力作用 被引量:1

Liguzinediol exerts positive inotropic effect by enhancing Ca^2+ release from sarcoplasmic reticulum mediated by sarcoplasmic reticulum Ca^+ATPase
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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)%〕。④LZDO(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�
作者 王伟 李莎 张梦丹 高颖 薛书银 陈可塑 王中越 陈龙 WANG Wei, LI Sha, ZHANG Meng-dan, GAO Ying, XUE Shu-yin, CHEN Ke-su, WANG Zhong-yue, CHEN Long ( 1. National Standard Laboratory of Pharmacology for Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210029, China; 2. Department of Respiratory Disease, Inpatient Wards for Senior Cadres, Nanjing General Hospital of Nanjing Military Command, Nanjing 210002, China;3. Institute of Chinese Medicine of Taizhou China Medical City, Taizhou 225300, China)
出处 《中国药理学与毒理学杂志》 CAS CSCD 北大核心 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)
关键词 LIGUZINEDIOL 钙释放 强心药 肌浆网钙转运ATP酶类 liguzinediol Ca^2+ release cardiotonic agents sarcoplasmic reticulum Ca^2+ ATPase
作者简介 王伟,男,硕士研究生,主要从事药物正性肌力机制研究,E-mail:631897525@qq.com,Tel:(025)85811193,15105107024 通讯作者:陈龙,E-mail:longchen@njutcm.edu.cn,Tel:(025)85811193.13584058521
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参考文献17

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