次乌头碱和甘草苷及甘草次酸配伍对急性心力衰竭大鼠的动态保护研究
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摘要
目的:研究附子甘草3种有效成分次乌头碱、甘草次酸、甘草苷对急性心力衰竭大鼠的保护作用,为深入探讨附子甘草配伍"强心减毒"的作用机制奠定药效学实验基础。方法:建立稳定的急性心力衰竭模型,随机将大鼠分为模型组,地高辛组,次乌头碱组,次乌头碱和甘草苷、甘草次酸配伍组(三药合用组)。十二指肠一次性给药,在造模后、给药后0、2、5、10、15、20、30、45、60min同步测定血流动力学指标,计算其变化率。结果:与模型组比较,三药合用组给药后2～20min显著改善急性心力衰竭大鼠的左心室舒张压(LVDP)、左心室内压下降最大速率(-dp/dtmax)(P<0.01,P<0.05),2～30min显著改善左室舒张末期压(LVEDP)、指标心率(HR)、左室内压上升最大速率(dp/dtmax)(P<0.01,P<0.05),并呈时-效关系。相较于次乌头碱组,三药合用组能显著拮抗次乌头碱导致的心律失常现象,10～15min显著改善LVDP(P<0.05),10～20min显著改善HR和LVEDP(P<0.05),10～30min显著改善dp/dtmax和-dp/dtmax(P<0.05,P<0.01)。结论:次乌头碱、甘草次酸和甘草苷配伍对急性心力衰竭大鼠有时效持久的强心作用,对次乌头碱产生的心率失常有拮抗作用。
Objective: To investigate on the protective effect of hypaconitine, glycyrrhetinic acid and glycyrrhizin which were the active ingredient of Aconiti Lateralis Radix Preparata and Glycyrrhizae Radix Et Rhizoma on acute heart failure in rats, and to lay a pharmacodynamic experimental foundation for further exploring the mechanism of compatibility of Aconiti Lateralis Radix Et Rhizoma Preparata and Glycyrrhizae Radix Et Rhizoma in ‘strengthening heart and reducing toxicity'. Methods: A stable model of acute heart failure was established. Rats were divided into four groups, including model group, Digoxin group, the hypaconitine group and the group which hypaconitine mix up with glycyrrhetinic acid and glycyrrhizin(the combination group). One-time administration of duodenum was taken and the hemodynamic parameters were measured at 0, 2, 5, 10, 15, 20, 30, 45 and 60 min after the establishment of the model and administration simultaneously. Hemodynamic indexes were measured simultaneously, and the rate of change was calculated. Results: Compared with the model group, the combination group could significantly improved the acute heart failure rats with diastolic blood pressure(LVDP), left ventricular pressure maximum rate of decline(-dp/dtmax) in 2-20 min(P<0.01, P<0.05), significantly improved left ventricular end diastolic pressure(LVEDP), the index of heart rate(HR), left ventricular pressure increases the rate of(dp/dtmax) in 2-30 min(P<0.01, P<0.05) after administration, which performed a time-effect relationship. Compared with the hypaconitine group, the combination group could significantly antagonize arrhythmia phenomenon caused by hypaconitine, significantly improved LVDP in 10-15 min(P<0.01, P<0.05), significantly improved HR and LVEDP in 10-20 min(P<0.05), and significantly improved-dp/dtmax and dp/dtmax in 10-30 min(P<0.05, P<0.01). Conclusion: The compatibility of hypaconitine and glycyrrhetinic acid and glycyrrhizin in the rats with acute heart failure has a long-lasting effect on the heart and an antagonistic effect on the cardiotoxicity induced by hypaconitine.
Objective: To investigate on the protective effect of hypaconitine, glycyrrhetinic acid and glycyrrhizin which were the active ingredient of Aconiti Lateralis Radix Preparata and Glycyrrhizae Radix Et Rhizoma on acute heart failure in rats, and to lay a pharmacodynamic experimental foundation for further exploring the mechanism of compatibility of Aconiti Lateralis Radix Et Rhizoma Preparata and Glycyrrhizae Radix Et Rhizoma in ‘strengthening heart and reducing toxicity'. Methods: A stable model of acute heart failure was established. Rats were divided into four groups, including model group, Digoxin group, the hypaconitine group and the group which hypaconitine mix up with glycyrrhetinic acid and glycyrrhizin(the combination group). One-time administration of duodenum was taken and the hemodynamic parameters were measured at 0, 2, 5, 10, 15, 20, 30, 45 and 60 min after the establishment of the model and administration simultaneously. Hemodynamic indexes were measured simultaneously, and the rate of change was calculated. Results: Compared with the model group, the combination group could significantly improved the acute heart failure rats with diastolic blood pressure(LVDP), left ventricular pressure maximum rate of decline(-dp/dtmax) in 2-20 min(P<0.01, P<0.05), significantly improved left ventricular end diastolic pressure(LVEDP), the index of heart rate(HR), left ventricular pressure increases the rate of(dp/dtmax) in 2-30 min(P<0.01, P<0.05) after administration, which performed a time-effect relationship. Compared with the hypaconitine group, the combination group could significantly antagonize arrhythmia phenomenon caused by hypaconitine, significantly improved LVDP in 10-15 min(P<0.01, P<0.05), significantly improved HR and LVEDP in 10-20 min(P<0.05), and significantly improved-dp/dtmax and dp/dtmax in 10-30 min(P<0.05, P<0.01). Conclusion: The compatibility of hypaconitine and glycyrrhetinic acid and glycyrrhizin in the rats with acute heart failure has a long-lasting effect on the heart and an antagonistic effect on the cardiotoxicity induced by hypaconitine.
引文
[1]要晓静.甘草附子汤化学成分分析.长春:吉林大学,2013
[2]苗潇磊,王俊俊,孟沫然,等.次乌头碱、甘草苷单用与合用对大鼠肝脏CYP450酶m RNA表达与活性的影响.中华中医药杂志,2016,31(1):313-316
[3]缪萍,裘福荣,曾金,等.甘草诱导CYP3A促进附子代谢的减毒配伍机制.中华中医药杂志,2014,29(9):2813-2817
[4]YANG Yan,YIN Xin-Juan,GUO Hui-Min,et al.Identification and comparative analysis of the major chemical constituents in the extracts of single Fuzi herb and Fuzi Gancao herb-pair by UFLC-IT-TOF/MS.Chinese Journal of Natural Medicines,2014,12(7):542-553
[5]周娟.次乌头碱在大鼠体内药代动力学及心脏分布研究.北京:北京中医药大学,2010
[6]Yin X,Xia G,Li Z,et al.Glycyrrhetinic acid attenuates lipopolysaccharide-induced fulminant hepatic failure in d-galactosamine-sensitized mice by up-regulating expression of interleukin-1 receptor-associated kinase-M.Toxicology&Applied Pharmacology,2017,320(2017):8-16
[7]Sun B,Zhang M,Zhang Q.Metabonomics study of the effects of pretreatment with glycyrrhetinic acid on mesaconitine-induced toxicity in rats.Journal of Ethnopharmacology,2014,154(3):839-846
[8]陈奇,孙建宁,林志彬,等.中药药理研究方法学.北京:人民卫生出版社,2006
[9]高妍,高建平.心力衰竭动物模型的研究进展.中成药,2014,36(1):148-152
[10]李志勇.附子成分次乌头碱心脏毒性及中毒机制研究.北京:北京中医药大学,2008
[11]Li-qin WANG,Yu-yan ZHANG,Hai-tong WAN,et al.Glycyrrhetinic acid protects H9c2 cells from oxygen glucose deprivation-induced injury through the PI3K/AKt signaling pathway.J Nat Med,2017,71:27-35
[12]Li-qin WANG,Yu HE,Hao-fang WAN,et al.Protective mechanisms of hypaconitine and glycyrrhetinic acid compatibility in oxygen and glucose deprivation injury.Journal of Zhejiang UniversitySCIENCE B(Biomedicine&Biotechnology),2017,18(7):586-596
[13]金敏,吴红金.甘草次酸对心肌缺血再灌注损伤的影响.中国药学杂志,2018,53(5):359-363
[14]Yasuyuki Shiraishi,Shun Kohsaka,Takayuki Abe,et al.Impact of triggering events on outcomes of acute heart failure.The American Journal of Medicine,2017,131(2):156-164
[15]邢冬梅,李彬,朱明军,等.中医药预防急性心肌梗死后心力衰竭的新思路.中华中医药杂志,2017,32(1):196-198
[16]Ishihara S,Gayat E,Sato N,et al.Similar hemodynamic decongestion with vasodilators and inotropes:systematic review,meta-analysis,and meta-regression of 35 studies on acute heart failure.Clinical Research in Cardiology,2016,105(12):971-980
[17]《临床医学研究与实践》编辑部.中国急性心力衰竭急诊临床实践指南(2017).临床医学研究与实践,2018,3(2):201
[2]苗潇磊,王俊俊,孟沫然,等.次乌头碱、甘草苷单用与合用对大鼠肝脏CYP450酶m RNA表达与活性的影响.中华中医药杂志,2016,31(1):313-316
[3]缪萍,裘福荣,曾金,等.甘草诱导CYP3A促进附子代谢的减毒配伍机制.中华中医药杂志,2014,29(9):2813-2817
[4]YANG Yan,YIN Xin-Juan,GUO Hui-Min,et al.Identification and comparative analysis of the major chemical constituents in the extracts of single Fuzi herb and Fuzi Gancao herb-pair by UFLC-IT-TOF/MS.Chinese Journal of Natural Medicines,2014,12(7):542-553
[5]周娟.次乌头碱在大鼠体内药代动力学及心脏分布研究.北京:北京中医药大学,2010
[6]Yin X,Xia G,Li Z,et al.Glycyrrhetinic acid attenuates lipopolysaccharide-induced fulminant hepatic failure in d-galactosamine-sensitized mice by up-regulating expression of interleukin-1 receptor-associated kinase-M.Toxicology&Applied Pharmacology,2017,320(2017):8-16
[7]Sun B,Zhang M,Zhang Q.Metabonomics study of the effects of pretreatment with glycyrrhetinic acid on mesaconitine-induced toxicity in rats.Journal of Ethnopharmacology,2014,154(3):839-846
[8]陈奇,孙建宁,林志彬,等.中药药理研究方法学.北京:人民卫生出版社,2006
[9]高妍,高建平.心力衰竭动物模型的研究进展.中成药,2014,36(1):148-152
[10]李志勇.附子成分次乌头碱心脏毒性及中毒机制研究.北京:北京中医药大学,2008
[11]Li-qin WANG,Yu-yan ZHANG,Hai-tong WAN,et al.Glycyrrhetinic acid protects H9c2 cells from oxygen glucose deprivation-induced injury through the PI3K/AKt signaling pathway.J Nat Med,2017,71:27-35
[12]Li-qin WANG,Yu HE,Hao-fang WAN,et al.Protective mechanisms of hypaconitine and glycyrrhetinic acid compatibility in oxygen and glucose deprivation injury.Journal of Zhejiang UniversitySCIENCE B(Biomedicine&Biotechnology),2017,18(7):586-596
[13]金敏,吴红金.甘草次酸对心肌缺血再灌注损伤的影响.中国药学杂志,2018,53(5):359-363
[14]Yasuyuki Shiraishi,Shun Kohsaka,Takayuki Abe,et al.Impact of triggering events on outcomes of acute heart failure.The American Journal of Medicine,2017,131(2):156-164
[15]邢冬梅,李彬,朱明军,等.中医药预防急性心肌梗死后心力衰竭的新思路.中华中医药杂志,2017,32(1):196-198
[16]Ishihara S,Gayat E,Sato N,et al.Similar hemodynamic decongestion with vasodilators and inotropes:systematic review,meta-analysis,and meta-regression of 35 studies on acute heart failure.Clinical Research in Cardiology,2016,105(12):971-980
[17]《临床医学研究与实践》编辑部.中国急性心力衰竭急诊临床实践指南(2017).临床医学研究与实践,2018,3(2):201
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