异丙嗪对豚鼠心脏电生理活动的影响  

Effect of promethazine on electrophysiological action of guinea pig hearts

作　　者：尚文斌[1] 罗卓卡[2] 李雪华[3] 刘磊[3] 王伟[3] 陈可塑[4] 王中越 陈龙[3,5] 

机构地区：[1]南京中医药大学第一临床医学院临床医学实验中心,江苏南京210046 [2]常州市第四人民医院,江苏常州213032 [3]南京中医药大学国家科技部规范化中药药理实验室,江苏南京210046 [4]南京大学金陵学院,江苏南京210089 [5]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》2014年第5期691-696,共6页Chinese Journal of Pharmacology and Toxicology

基　　金：江苏省基础研究计划(自然科学基金)项目(BK21031262);江苏省高校自然科学研究重大项目(14KJA360002)~~

摘　　要：目的研究异丙嗪致心律失常的作用及其机制。方法 1豚鼠在体心脏实验:按照顺序累加静脉推注异丙嗪盐酸盐0.5,1,3和5倍临床剂量,即3.83→7.67→15.33→38.33 mg·kg-1的顺序累加静脉推注,每组持续5 min,于处理后5 min后记录心电图。2豚鼠离体心电图实验:按照顺序灌流异丙嗪盐酸盐0.1→1→10→50μmol·L-1。上一浓度灌流结束后随后灌流下一浓度,每一组灌流持续5 min,分别记录各浓度组给药5 min后的心电图。3记录豚鼠左心室肌细胞L型钙电流实验:按照顺序灌流异丙嗪盐酸盐0.1→1→10→50μmol·L-1,每一组灌流持续5 min,分别记录各浓度组给药5 min后的L型钙电流。4记录HEK细胞表达的hNav1.5和hERG电流:记录hNav1.5电流按照异丙嗪1→3→10→30μmol·L-1的顺序灌流,记录hERG电流按照异丙嗪0.3→1→3→10μmol·L-1的顺序灌流,于灌流的5 min末记录各自的电流。结果 1在体心电图结果表明,异丙嗪15.35 mg·kg-1剂量显著延长QRS间期(P<0.05);38.33 mg·kg-1延长QRS,QTc和P-R间期并减慢心率(P<0.05)。2异丙嗪10μmol·L-1明显减慢离体豚鼠心脏心率(P<0.05);50μmol·L-1明显延长QRS和QTc间期(P<0.05)。3异丙嗪盐酸盐阻滞大鼠心室肌细胞L型钙电流呈浓度依赖性,其抑制L型钙电流的IC50为(8.9±1.0)μmol·L-1。4异丙嗪抑制hNav1.5及hERG通道呈浓度依赖性,其IC50分别为(6.1±1.5)和(1.6±0.2)μmol·L-1。结论异丙嗪临床剂量的使用较为安全,但当剂量过大或与其他具有抑制钾、钠和钙通道药物合用时易导致严重的心律失常。抑制心肌钾、钠和钙通道是其致心律失常的作用机制。OBJECTIVE To explore the effect and underlying mechanism of promethazine（PMZ） on proarrhythmia in guinea pigs. METHODS ① InvivoECG recordings were made to analyze effects of jugular intravenous（iv）injection of PMZ on ECG in guinea pigs. PMZ was injected in this order：3.83→7.67→15.33→38.33 mg·kg-1 cumulatively. ② In vitroECG recordings were made to analyze effects of PMZ on ECG in isolated hearts of guinea pigs. PMZ was perfused in such order：0. 1 → 1 → 10 →50 μmol·L-1 . ③ L-type Ca2＋ currents from ventricular myocytes in guinea pigs were recorded to investi-gate the PMZ＇s blocking effect. PMZ was perfused in such order：0.1→1→10→50 μmol·L-1→washout.④ hNav1.5 and hERG currents were recorded to investigate the PMZ＇s blocking effects. PMZ-perfused in such order：1→3→10→30 μmol·L-1 for hNav1.5 current analysis,and 0.3→1→3→10 μmol·L-1 for hERG current analysis. RESULTS ① PMZ（15.33 mg·kg-1 ）significantly prolonged QRS intervals in guinea pigs invivoECG（P﹤0.05）. PMZ（38.33 mg·kg-1 ）prolonged QRS,QTc,and P-R intervals but reduced the heart rate（ P﹤0.05）. PMZ（10 μmol·L-1 ）reduced the heart rate of isolated guinea pig hearts. PMZ 50 μmol·L-1 prolonged QRS and QTc intervals and further reduced the heart rate（P﹤0.05）.③ PMZ inhibited the L-type Ca2＋ current from ventricular myocytes in guinea pigs in a concentration-dependent manner with the lC50 of（8.9±1.0）μmol·L-1 . ④ PMZ inhibited the hNav1.5 and hERG currents in a concentration-dependent manner with the lC50 of 6.1±1.5 and（1.6±0.2）μmol·L-1 ,respectively. CONCLUSION PMZ might cause arrhythmia at overdoses and incombination with other drugs which have potential blocking effect on /Na ,Ca2＋ and /kr currents. The proarrhythmic effect of PMZ might be mediated by the blocking effect on /Na ,Ca2＋ and /kr currents.

关 键 词：异丙嗪 心电图 心律失常 HERG 电流 

分 类 号：R965[医药卫生—药理学]