【作者】 于晓明；

【导师】 杨传华；

【作者基本信息】 山东中医药大学 ， 中医内科学， 2012， 博士

【摘要】 目的：探讨快律宁（以下简称为KLN）胶囊对大鼠离体心脏心室肌细胞电生理的影响及有无促心律失常的风险，探讨KLN胶囊对外源性自由基所致心律失常的影响并分析其作用机制。方法：实验一：将SPF级SD大鼠分为对照组、普罗帕酮组和KLN胶囊高、中、低剂量组，将对照组分别与用药组进行组间比较，将普罗帕酮组与KLN三个剂量组进行组内比较。1.观察KLN胶囊对大鼠离体心室肌细胞动作电位APD50、APD90、APA、VMAX、EAD等电生理指标，分析其作用机制；2.分别将各组用药前后的RR间期、QT间期、QTc进行比较，分析KLN胶囊有无促心律失常的风险。实验二：将SPF级SD大鼠分为对照组、维拉帕米组和KLN胶囊高、中、低剂量组，采用Langendoff灌流装置对大鼠离体心脏灌注硫酸亚铁/抗坏血酸的方法，复制外源性自由基所致大鼠心律失常模型，对比研究KLN胶囊与维拉帕米对其的保护作用。结果：实验一：1.与对照组相比，KLN胶囊高、中剂量组的APD50、APD90均有延长（p<0.01），而且具有剂量依赖性。低剂量组则不明显(p>0.05)。组内比较显示，普罗帕酮组的APD50、APD90均长于KLN胶囊三个剂量组（P<0.01）。2.与对照组相比，KLN胶囊可以剂量依赖的减小VMAX，其中高、中剂量组减小尤为明显（P<0.01），组内比较显示，KLN胶囊三个剂量组与普罗帕酮的VMAX无显著性差异（P>0.05）。3.与对照组相比，KLN胶囊可以剂量依赖的降低APA，组内比较显示普罗帕酮组的APA与KLN胶囊中低剂量相比有显著差异,普罗帕酮组的APA较低(P<0.01),与高剂量组相比则无显著性差异（P>0.05）。4.KLN胶囊高中低三个剂量组的R-R间期用药后均有显著延长（P<0.05），而且呈剂量依赖性。5.KLN胶囊三个剂量组用药前后的QT间期及QTc无显著性差异（P>0.05）。6.普罗帕酮组用药后的RR间期、QT间期和QTc均有显著延长（P<0.05））7.KLN胶囊三个剂量组在灌流过程中均未诱发EAD，普罗帕酮组则有4例出现了EAD，经统计EAD发生率有显著性差异（P<0.01）。实验二：1.与对照组相比，KLN胶囊可以剂量依赖的减少对外源性自由基所诱发VEB、VT的发生次数（P<0.01）。2.KLN胶囊三个剂量组及维拉帕米组均未出现VF，而对照组则诱发出VF，但经统计无显著性差异(P>0.05)。3.与对照组相比，KLN胶囊高剂量组心律失常的出现时间较晚（P<0.05）,而KLN胶囊中低剂量组、维拉帕米组心律失常的出现也有推迟的趋势，但经统计无显著性差异(P>0.05)。4.与对照组相比，KLN胶囊三个剂量组的心率明显减慢，而且呈剂量相关性。5.与对照组性比，KLN胶囊高、中剂量组的心律失常评分明显降低（P<0.05）,而KLN胶囊低剂量组和维拉帕米组则与对照组无显著性差异(P>0.05)。结论：1.KLN胶囊可以剂量依赖的对正常大鼠离体心脏电生理产生影响，而对QT间期无影响，因此可能具有较低的致心律失常的风险。2.KLN胶囊对外源性自由基诱发的心律失常可能具有预防和治疗作用，可以明显减慢心率，并可能对恶性心律失常（VT、VF）的发生具有一定的预防和治疗作用，其疗效优于维拉帕米。3．KLN胶囊抗快速型心律失常的机制可能与同时作用于钾通道、钠通道，钙通道有关，同时可能对自由基具有清除作用，抑制钙超负荷，可能具有多靶点治疗作用特点，是一种类似于Ⅲ类和Ic类和IV类复合作用的抗心律失常药物，因此对快速型心律失常可能具有很好的疗效，并可能具有较低的致心律失常的风险，具有很好的研究前景。更多还原

【Abstract】 Objective: To investigate the KLN (hereinafter referred to as the KLN) capsules onthe isolated rat heart ventricular myocytes electrophysiological and whether to promote therisk of arrhythmia to explore the impact the KLN capsule of exogenous free radicalscaused by arrhythmia analysis of its mechanism of action.Methods:Experiment1: SPF SD rats were divided into control group, propafenone group andKLN capsule high, medium, low-dose group, the control group and treatment groupbetween the two groups, compared the propafenone group with KLN three dose groups.1.Observation the KLN capsule action potential of isolated rat ventricular myocytesthe APD50, APD90, APA, VMAX, EAD and other electrophysiological parameters, analysisof its mechanism of action.2.Respectively in each group before and after treatment, RR interval, QT interval,QTc, which were compared and analyzed the risk of KLN capsules without promotingarrhythmias.Experiment2: SPF SD rats were divided into control group and the verapamil groupand the KLN capsule high, medium, low-dose group, Langedoff perfusion apparatus forisolated rat heart perfusion ferrous sulfate/ascorbic acid method, copy the exogenous freeradicals induced arrhythmia model, compared to its protective effect of the KLN capsule ofverapamil.Results:Experiment1:1.Compared with the control group, the KLN capsule high, medium-dose group of theAPD50, APD90of both prolonged (p <0.01), and these dose were dependent. Low-dose group was not significant (p>0.05). Comparison group, the propafenone group the APD50,APD90were longer than the KLN capsules three dose groups (P <0.01).2.Compared with the control group, the KLN capsule dose-dependent decreases VMAX,which high-dose group decreases, especially (P <0.01). From group showed, the KLNcapsules three dose groups with propafenone VMAXhad no significant differences (P>0.05).3.Compared with the control group, the lower the APA the KLN capsules can be adose-dependent group comparison shows that in the propafenone group APA KLN capsulelow dose compared to significant differences in the propafenone group APA lower (P<0.01) compared with the high dose group had no significant difference (P>0.05).4.The KLN capsule high medium and low-dose group RR interval after treatmentwere significantly prolonged (P <0.05) and dose-dependent manner.5.The KLN capsules before and after administration of three dose groups of QT andQTc were no significant difference (P>0.05).6.After administration of propafenone group, RR interval, the QT interval and QTcwere significantly prolonged (P>0.05).7.Perfusion process, the KLN capsules three dose groups were not induced by theEAD, the propafenone group had four cases of EAD, which statistics EAD had incidencesignificant difference (P <0.01).Experiment2:1.Compared with the control group, the KLN capsule dose-dependent reduction ofexogenous free radicals induced of VEB, VT occurrence (P <0.01).2.The KLN capsule three dose group and verapamil group were not VF control groupinduced the VF, but no significant statistical difference (P>0.05).3.Compared with the control group, the KLN high dose group arrhythmia appear later(P <0.05). The KLN capsule medium and low-dose group, verapamil group of arrhythmiasalso postponed, but statistics had no significant difference (P>0.05).4.Compared with the control group the KLN capsule three dose groups heart rateslowed down, and was dose-related.5.And control groups KLN capsule high and medium-dose group arrhythmia scorewas significantly lower (P <0.05), while the KLN capsule low dose group, verapamil groupand the control group, had no significant difference (P>0.05).Conclusion: 1.The KLN capsule dose-dependent impact on the normal rat in vitro cardiacelectrophysiology had no effect on the interval QT. Therefore it may have a lowerarrhythmogenic risk.2.The KLN capsule exogenous free radical-induced arrhythmias may have preventiveand therapeutic effect. It can significantly slow down the heart rate, and may have somepreventive effect to the occurrence of malignant ventricular arrhythmias (VT, VF). Itsefficacy is superior Verapamil.3.KLN Capsule of Tachyarrhythmia mechanism may be simultaneously related topotassium channels, sodium channels, calcium channels. It may be both free radicalsscavenging effect, inhibition of calcium overload. It may have a role of the characteristicsof multi-target therapy, which is a similar to the composite role of class III, class Icandclass IV anti-arrhythmic drugs. Tachyarrhythmia may have a good effect, which may havea lower arrhythmogenic risk with good prospects.更多还原