【作者】 李东娜；

【导师】 杨传华；

【作者基本信息】 山东中医药大学 ， 中医内科学， 2013， 博士

【摘要】 目的观察快律宁（KLN）对犬冠脉结扎所致缺血性室性心律失常以及对豚鼠心室肌细胞钾通道的影响，评价KLN对急性缺血性心律失常的作用，初步探讨KLN抗心律失常的可能的离子机制。方法1.Beagle犬经适应性饲养5天后随机分为模型对照组（生理盐水）、实验组（KLN0.7695g/kg）、阳性对照组（普罗帕酮50mg/kg）。采用犬冠状动脉两步结扎法复制快速性心律失常模型。冠脉结扎后约13小时，室性心律失常情况较稳定，此时灌胃给药，以多导生理信号采集分析系统分别记录给药前及给药后30min、60min、90min、120min、180min和240min的心电图变化。2.采用Langendorff灌流装置消化分离单个豚鼠心室肌细胞，以全细胞膜片钳方式记录给药前后细胞延迟整流钾电流（IK）、内向整流钾电流（IK1）波形，观察通道电流的变化。结果1. KLN对急性缺血性心律失常的影响：①室性早搏（PVC）：实验组在给药后30～240min内显著减少PVC次数，与模型对照组相比有统计学差异（P<0.01或P<0.05），与阳性对照组间差异无统计学意义（P>0.05）。KLN对PVC的抑制率最高达54.31±17.2%。②室性心动过速（VT）：实验组在给药后30～240min皆显著减少VT时间，与模型对照组相比有统计学差异（P<0.01或P<0.05），与阳性对照组间差异无统计学意义（P>0.05）。KLN对VT时间的抑制率最高达60.42±31.63%。2. KLN对豚鼠心室肌细胞钾通道的影响：①IK：低、中、高剂量KLN（2.5mg/ml、5mg/ml、10mg/ml）作用5min后均可使IK及其尾电流（IK,tail）的电流幅度降低，电流密度-电压关系曲线下移；KLN能显著抑制IKs及IKs, tial（P<0.01或P<0.05），作用呈剂量依赖性；envelope of tails test测得，低、中、高剂量KLN均可显著降低IK,tail电流（P<0.01），使电流密度-时间关系曲线下移，作用呈剂量依赖性。②IK1：低剂量KLN对IK1无明显作用（P>0.05），中、高剂量KLN可显著降低IK1内向电流（P<0.01）；高剂量KLN对IK1外向电流有抑制作用（P<0.05）。结论1. KLN有一定的抗急性缺血性心律失常的作用，在给药后30-240min内可持续作用，120-180min左右作用较强。2. KLN对IK具有剂量依赖性抑制作用，高剂量KLN可抑制IK1内、外向电流，这可能是其发挥抗心律失常作用的机制之一。更多还原

【Abstract】 Object：To observe the effect of KLN on canine coronary ligation-induced ventriculararrhythmias, and the effect on guinea pig ventricular myocytes potassium channel, in orderto evaluate the effect of KLN on acute ischemic arrhythmias and to explore the possibleionic mechanisms of KLN.Methods：1. Beagle dogs were randomly divided into model control group (normalsaline), experimental group (KLN0.7695g/kg) and positive control group (propafenone50mg/kg) after5days adaptive feeding. Anterior descending coronary artery was ligated asa two-step ligation to copy the tachyarrhythmia model.13hours later, gave KLN andrecorded ECG before and after the administration at30min,60min,90min,120min,180min and240min.2. The Langendorff perfusion device was used for the digestion andseparation of single guinea pig ventricular myocytes. The ventricular myocytes delayedrectifier potassium current (IK) and inward rectifier potassium current (IK1) were recordedat whole cell patch clamp recording mode before and after the administration of KLN.Observe the changes of IKand IK1currents’ waveform.Results：1. Effect of KLN on acute ischemic arrhythmias:①Premature ventricularcomplexes (PVC):30~240min after the administration of KLN, the PVC number wassignificantly reduced (compared with the model group, P<0.01or P<0.05). Theexperimental group and the positive control group showed no significant difference(P>0.05). KLN could inhibit PVC at54.31±17.2%at the most.②Ventricular tachycardia(VT):30~240min after the administration of KLN, VT time was significantly reduced(compared with the model group, P<0.01or P<0.05). The experimental group and thepositive control group showed no significant difference (P>0.05). KLN could inhibit PVCat60.42±31.63%at the most.2. Effect of KLN on guinea pig ventricular myocytes potassium channel:①IK: low, medium and high dose KLN (2.5mg/ml,5mg/ml,10mg/ml)reduced IKtail current (IK,tail) after5min, made the current density-voltage relationshipcurve down. KLN significantly inhibited IKsand IKs,tial(P<0.01or P<0.05) in adose-dependent manner. Envelope of tails test showed low, medium and high dose KLNsignificantly reduced IK,tailcurrent (P<0.01) in a dose-dependent manner, and made thecurrent density-time curve down.②IK1: low dose KLN showed no significant effect onIK1(P>0.05). Medium and high dose KLN significantly reduced IK1inward current(P<0.01). High doses KLN reduced IK1outward current (P<0.05).Conclusion：1. KLN showed significant effect on acute ischemic arrhythmia. Itseffect lasted from30min to240min after administration, and was stronger between120-180min.2. KLN has a dose-dependent inhibition on IK. High dose KLN also reducedthe inward and outward current of IK1. Which may be the mechanisms of KLN’santiarrhythmic effect.更多还原