目的 比较高乌甲素及其水解产物的心脏毒性及抗心律失常活性，明确C-4位芳香取代基对其活性和毒性的影响。方法 采用碱水解、硅胶柱色谱以及波谱法对高乌甲素水解产物进行分离鉴定；采用心脏毒性实验和乌头碱诱发心律失常模型，比较高乌甲素及其水解产物的毒性和活性。结果 分离并鉴定出高乌甲素水解产物为刺乌宁；股iv 2.40 mg/kg高乌甲素可引起大鼠出现室性早搏（ventricular premature beat，VPB）、室性心动过速（ventricular tachycardia，VT）等心律失常现象，刺乌宁在相同剂量下未出现心律失常现象；在抗心律失常活性研究中，高乌甲素、刺乌宁在各自的剂量范围内，随着剂量的增大，VPB潜伏期延长，VT发生率降低，心律失常完全抑制率逐渐升高，呈剂量相关性，表明两者均有一定的抗心律失常作用，高乌甲素的作用强于刺乌宁。结论 与高乌甲素相比，随着C-4位芳香取代基的水解，水解产物刺乌宁的心脏毒性降低，抗心律失常活性明显减弱，表明C-4位芳香取代基是高乌甲素产生心脏毒性、发挥药效的关键基团。

Objective To compare the cardiotoxicity and antiarrhythmic activity of lappaconitine and its hydrolysate, and clarify the effect of aromatic substituent at C-4 position on activity and toxicity. Methods The hydrolysis product of lappaconitine was separated and identified by alkaline hydrolysis, silica gel column chromatography and spectroscopic method. Furthermore, cardiotoxicity assay and aconitine-induced arrhythmia model were used to compare the toxicity and activity of lappaconitine and its hydrolysate. Results Lappaconine, the hydrolysate of lappaconitine, was isolated and identified. Intravenous injection of 2.40 mg/kg lappaconitine induced ventricular premature beat (VPB) and ventricular tachycardia (VT) in normal rats, but no arrhythmias were observed when administration of the same dose of lappaconine. In the study of antiarrhythmic activity, in the respective dose range of lappaconitine and lappaconine, they could dose-dependently delay the onset time of VPB, reduce the incidence of VT, combined with the increasing arrhythmia inhibition rate and exhibiting antiarrhythmic activities. Meanwhile, lappaconitine had a better antiarrhythmic effect than lappaconine. Conclusion Compared with lappaconitine, with the hydrolysis of aromatic substituent group at C-4 position, the cardiotoxicity of hydrolysate lappaconine is reduced, and antiarrhythmic activity is obviously diminished, which demonstrates that the aromatic substituent at C-4 position is a key group for cardiotoxicity and antiarrhythmic effect.

R285.5

国家自然科学基金资助项目（81403104）；四川省科技厅省级科技计划项目（2020YJ0131）；成都中医药大学“杏林学者”学科人才科研提升计划（QNXZ2018042）