蛋白磷酸酶(PP1、PP2A)抑制剂Calyculin A对大鼠心脏血流动力学的影响  

Studies on hemodynamic effects of Calyculin A of protein phosphatase 1 and 2A inhibitor and its underlying mechanism in rats

作　　者：黄惠丽[1] 谢铭[1] 高丽 张文慧 陈可塑[2] 刘福明 陈龙[1,4] HUANG Hui-li;XIE Ming;GAO Li;ZHANG Wen-hui;CHEN Ke-su;LIU Fu-ming;CHEN Long(National Standard Lab of Pharmacology for Chinese Materia Medica,School of Pharmacy,Nanjing University of Chinese Medicine,Nanjing 210023,China;Dept of Respiratory Diseases,Inpatient Wards for Senior Cadres,Nanjing General Hospital of Nanjing Military Command Region,Nanjing 210002,China;First Affiliated Hospital,Nanjing University of Chinese Medicine,Nanjing 210029,China;Institute of Chinese Medicine of Taizhou China Medical City,Taizhou Jiangsu 225300,China)

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,江苏南京210023 [2]南京军区总医院干部病房呼吸科,江苏南京210002 [3]南京中医药大学附属医院江苏省中医院心脏内科,江苏南京210029 [4]泰州中国医药城中医药研究院,江苏泰州225300

出　　处：《中国药理学通报》2018年第12期1697-1702,共6页Chinese Pharmacological Bulletin

基　　金：泰州中国医药城第四批"113人才计划"(No 2016024);江苏省自然科学基金资助项目(No BK20151355)

摘　　要：目的研究蛋白磷酸酶(PP1、PP2A)抑制剂Calyculin A对大鼠血流动力学的作用及其心肌细胞钙释放的特征。方法采用大鼠在体双压力(P-V loop)导管分析心脏血流动力学及主动脉压;采用场刺激的方法分析心肌细胞钙释放。结果左侧颈静脉给予Calyculin A(0. 8μg·kg-1)明显提高左心室收缩力,表现为明显增加左心室搏出功、心输出量、每搏输出量、射血分数、收缩末期压力-容积关系曲线斜率;明显改善心脏舒张功能,表现为明显降低左心室舒张末期压力-容积关系曲线斜率;增加主动脉收缩压、舒张压及脉压差; Calyculin A(100 nmol·L-1)明显增加心肌细胞钙释放的幅值及缩短钙回吸收拟合曲线的时间常数。结论 Calyculin A的正性肌力作用与肌浆网钙泵活性有关,蛋白磷酸酶(PP1、PP2A)可作为潜在靶点,用于开发正性肌力药物。Aim To study the hemodynamic effects of Calyculin A, an inhibitor of protein phosphatase 1 and 2A, in normal rats and characterize its effect on Ca 2＋ transient from ventricular myocytes. Methods The techniques of P-V loop was employed to assess cardiac hemodynamics and aorta pressure in rats, and field stimulation was used to analyse calcium release from cardiomyocytes. Results Calyculin A （0.8 μg·kg^ -1 ） administered intravenously significantly enhanced the positive inotropy and improved the diastolic function of left ventricle by increasing stroke work, cardiac output, stroke volume, ejection fraction, the slope of the left ventricular end-systolic P-V relationship （Ees） and by decreasing the slope of the left ventricular end- diastolic P-V relationship （Eed）. Meanwhile, Calyculin A （0.8 μg·kg -1 ） increased the systolic blood pressure, diastolic blood pressure and pulse pressure. Also, Calyculin A （100 nmol·L^-1 ） remarkably enhanced the amplitude of Ca ^2＋ transient, lowered the diastolic Ca ^2＋ concentration of cytoplasm and shortened the time constant of single exponential decay curve of Ca ^2＋ reuptake. Conclusions Calyculin A exerts the effect of positive inotropy and enhances the SR Ca^ 2＋ reuptake via promoting the activity of SERCA2a. The protein phosphatase 1 and 2A might serve as a potential target for developing inotropic agent for treating heart failure.

关 键 词：蛋白磷酸酶 Calyculin A 正性肌力 钙释放 血流动力学 压力-容积环 

分 类 号：R-332[医药卫生] R322.11