【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。更多还原

【Abstract】 OBJECTIVE To explore the effect and underlying mechanism of promethazine( PMZ) on proarrhythmia in guinea pigs. METHODS 1 In vivo ECG 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-1cumulatively. 2 In vitro ECG 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 investigate 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-1for hNav1. 5 current analysis,and 0. 3→1→3→10 μmol·L-1for hERG current analysis. RESULTS 1 PMZ( 15. 33 mg·kg-1) significantly prolonged QRS intervals in guinea pigs in vivo ECG( 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-1prolonged 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 IC50of( 8. 9 ±1. 0) μmol·L-1.4 PMZ inhibited the hNav1. 5 and hERG currents in a concentration-dependent manner with the IC50of6. 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 INa,Ca2 +and Ikr currents. The proarrhythmic effect of PMZ might be mediated by the blocking effect on INa,Ca2 +and Ikr currents.更多还原