【作者】 高飞；

【导师】 张季谦；

【作者基本信息】 安徽师范大学 ， 原子与分子物理， 2013， 硕士

【摘要】 多年来，生物医学领域的实验研究显示，哺乳动物的心室电生理活动，是由心室细胞膜上的各种跨膜离子电流(主要有Na+、K+、Ca2+等离子)共同参与而完成的。正是由于这些离子的共同参与，使各种离子电流保持着微妙的平衡，从而使心室能够完成正常的电生理活动；然而，心室的电生理活动也受细胞内外环境变化的影响，以人体心室为例，低血钾、电解质紊乱及药物中毒、严重缺氧、缺血、器质性心脏病等，这些症状都可能引起细胞内外离子浓度的异常，进而影响心室的电生理活动，使心室动作电位时程显著地降低，产生快速的心室速率，导致心跳加速，形成室性心律失常，例如，室性心动过速、心室扑动与心室颤动等症状，严重时直接影响人体的生命安全。心室作为心脏传导系统的主要传导组织，对室性心律失常症状的产生起到决定性的作用。而临床实验研究显示，钾离子电流在治疗室性心律失常有着重要的作用。因而，在室性心律失常条件下，模拟钾离子电流对心室电生理活动的影响，对相关生物医学研究有着重要的借鉴意义和参考价值。本文利用犬心室细胞组织电生理活动模型进行数值模拟，探讨了室性心律失常条件下，适当或过度阻滞心室钾电流对室性心律失常的影响及内在机理；同时，考察了晚钠电流及细胞外钠离子浓度对过度阻滞钾离子电流而产生的药物诱导室性心律失常症状的调控作用。论文的第一部分，介绍了与本文研究内容相关的基本思想和基本知识，包括控制量与动力学问题简述、生物细胞膜离子通道、心室细胞组织的电生理活动等内容。论文的第二部分，简要介绍了本文所使用的心室实验模型，并对模型中引入表达钾电流的倍数因子λ及有关公式作了说明；经过仿真模拟得出适当或过度阻滞钾离子通道电流对室性心律失常的影响；同时，进一步分析了，过度阻滞钾离子通道电流导致早期后除极(earlyafterdepolarization; EAD)产生的内在机理。结果显示，当适当阻滞钾离子通道电流时(即调节参数λ>0.67，阻滞钾离子电流小于43%时)，可以减轻甚至消除心律失常现象；然而，过度阻滞钾通道电流(即调节参数λ<0.67)，例如，当λ=0.1时，导致EAD的产生，加重室性心律失常症状。论文的第三部分，考察了调控晚钠电流及细胞外钠离子浓度对EAD的作用效果。在原模型中引入参数λ NaL(λ NaL是细胞膜晚钠电流的倍数)、λ Nao(λ Nao是细胞外钠离子浓度的倍数)，我们固定参数λ=0.1不变，使体系处在出现EAD的症状，调节参数λ NaL、λ Nao，参数λ NaL、λNao的变化范围分别为0.1~1.0；分析对比各个参数范围上能否很好地消除EAD现象。结果显示，当阻滞晚钠电流达到80%时(即λ NaL=0.2时)，可以明显的消除EAD现象。因雷诺嗪是阻滞晚钠电流的特效药(其有效治疗范围为2~6μ mol L，在犬心室细胞中IC50=6μmol L)，当λ NaL=0.2时，远超出雷诺嗪的有效治疗范围；当降低细胞外钠离子浓度时，即调控参数λ Nao=0.55时，能够很好的消除EAD现象，但此方法使细胞外钠离子浓度降低过多，可能引起其它疾病；当采用阻滞晚钠电流的同时也降低细胞外钠离子浓度时，能够很好的消除EAD现象，且晚钠电流也在其有效疗程范围内，能够很好的发挥其特效药作用，同时降低细胞外钠离子浓度也在生理允许的范围内；为了能更好的反映同时调控晚钠电流和细胞外钠离子浓度是否能够很好的消除EAD现象，我们引入心室复极的离散性(Beat-to-beat variability ofrepolarization, BVR)概念。结合BVR，并给出调控晚钠电流和细胞外钠离子浓度合理的区间。这一结果表明，当EAD产生时，我们可以通过调节晚钠电流和细胞外钠离子浓度等方法来减轻或消除这种负面影响。更多还原

【Abstract】 For years, the experimental research in the biomedical field showsthat the electrophysiological activity of mammal`s heart ventricle isaccomplished by many kinds of ion currents(such as sodium ion,potassium ion, calcium ion etc.) which distribute in the ventricle cellmembrane. Because of these ions to participate, a delicate balance couldbe maintained among different types of ion current, and the ventriclenormal electrophysiological activity could be accomplished; However,the ventricle electrophysiological activity is also affected by the changesof the internal and external environment of the cell. Taking the humanventricle as an example, hypokalemia, electrolyte disturbance, drugpoisoning, severe hypoxia, ischemia, organic heart disease and so on.These symptoms could cause the abnormal ion concentration inside andoutside the cell, affect the ventricular electrophysiological activity,significantly reduce the ventricular action potential duration, and producerapid ventricular rate, leading to a rapid heartbeat, engender theventricular arrhythmia, such as ventricular tachycardia, ventricular flutterand ventricular fibrillation and other symptoms, seriously affect thehuman life. Ventricular as the main conduction organizations of the heartconduction system, and it plays a decisive role on ventricular arrhythmia. Experimental study in vitro reveals that potassium ion current plays animportant role in the treatment of ventricular arrhythmias.So it has an important reference significance and reference value forbiomedicine study about the simulation of potassium ion current onventricular electrophysiological activity under the condition of ventriculararrhythmia. By using the model of canine ventricular, we have discussedthe effect of appropriately or excessively inhibited the potassium currenton ventricular cell under the condition of ventricular arrhythmia, andstudied the controlling of later sodium current and extracellular sodiumion concentration on ventricular arrhythmia symptoms which induced byexcessively inhibited the potassium current.The first chapter of this paper introduced concerned basic thoughtand knowledge, including control quantities and kinetic problems, ionchannels, ventricular tissue physiological activities, etc.The second chapter presentated the model of canine ventricular,potassium current multiple factor λ is introduced and the relevantformula is described. After the simulation, we have learned the effect ofappropriately or excessively blocking potassium ion channel currents onventricular arrhythmia; At the same time, the early afterdepolarization(early after depolarization; EAD) internal mechanismcaused by excessively suppress potassium current was further analysised.The results show that if the potassium current blocked appropriately (adjust the parameter λ>0.67, block potassium current less than43%),ventricular arrhythmia could be reduced and even be eliminated thephenomenon of arrhythmia. However, if the potassium current inhibitedexcessively (adjust parameter λ <0.67), for example, if λ=0.1, lead toEAD, increase the symptomatic of ventricular arrhythmia.At the last chapter, we investigated the effect on EAD by regulatedthe late sodium current and extracellular sodium ion concentration. In theoriginal model, we introduced the parametersλ NaL(multiple factors oflate sodium current),λ Nao(multiple factors of extracellular sodium ionconcentration), the parameter λ=0.1was fixed, and make the system atthe symptoms of EAD, then regulated the parametersλ NaLandλ Nao, theparameters ofλ NaL、λ Naorange are0.1~1.0, respectively; then thevarious parameters whether eliminate the phenomenon of EAD wereanalysised. According to the results, when the late sodium current wasblocked reached to80%(ifλ NaL=0.2), could significantly eliminate thephenomenon of EAD. Ranolazine is a specific drug blocking late sodiumcurrent(Its scope of effective treatment is2~6μ mol L, in canineventricular cellsIC50=6μmol L), ifλ NaL=0.2, This data is far beyond thescope of its effective treatment; If reduced extracellular sodium ionconcentration, when regulated the parameterλ Nao=0.55, EAD could beeliminated very well, but extracellular sodium ion concentration reducedtoo much, may cause other diseases; By blocking late sodium current and reducing the extracellular sodium ion concentration at the same time,EAD could be eliminated, blocking the late sodium current in the range ofits effective treatment, ranolazine could play its specific drug role, anddecreasing the extracellular sodium ion concentration in the physiologicalallowed range, also; In order to reflect the EAD could be well eliminatedby regulating late sodium and extracellular sodium ion concentration atthe same time, We introduce a concept of the discrete of ventricularrepolarization (Beat-to-beat variability of repolarization, BVR).Combining BVR, the reasonable range of control late sodium current andextracellular sodium concentration was given. The results show that,when EAD occurs, we may be able to reduce or eliminate the negativeeffects by adjusting the late sodium current and the extracellular sodiumconcentration, as well as other methods.更多还原