摘要
第一部分局部给药跨室壁氯化钾单相动作电位记录电极的研制
目的：研制可局部给药跨室壁氯化钾单相动作电位(MAP)记录电极(KCl MAP电极)，以稳定同步记录三层心肌的MAP；探讨电极的放置方法、记录MAP的稳定性和持续时间；探讨通过电极局部给药的可行性；为在体犬跨室壁复极不均一性与室性心律失常机制的研究提供理想的技术手段。
方法：由5F动脉鞘管和0.2mm的绝缘银丝，组构成3对MAP记录电极，鞘芯腔内注入含30％氯化钾琼脂糖凝胶即制成KCl MAP电极。用自制的电极记录在体犬左心室前壁跨窒壁MAP，观察通过电极局部给予异丙肾上腺素对三层心肌细胞动作电位时程(APD)及跨室壁复极离散度(TDR)的影响和心律失常的诱发情况。
结果：KCl MAP电极能稳定记录三层心肌MAP 120min以上，随时间的延长动作电位振幅(APA)逐渐降低但不影响复极特性的分析；局部给予异丙肾上腺素(10~(-5)mg／ml)能显著降低中层心肌细胞的APD_(90)(236.9±3.8ms vs 211.3±3.0ms)和TDR(35.7±4.8 ms vs 24.9±3.9 ms)，中层心肌细胞易于诱发早期后除极及触发活动并引起室性心律失常。
结论：KCl MAP电极可理想地用于跨室壁心肌复极特性的研究；异丙肾上腺素降低正常犬的TDR，其诱发室性心律失常的机制与后除极和触发活动有关。
第二部分局部异丙肾上腺素诱发在体犬室性心律失常电生理机制的研究
目的观察在体犬心室肌局部给予异丙肾上腺素后所产生的电生理现象，从跨室壁复极离散度(TDR)的角度探讨局部交感神经张力不均一性增加的致室性心律失常(VA)机制。
方法经自制跨室壁氯化钾单相动作电位记录电极(KCl MAP电极)于左心室前壁局部给予异丙肾上腺素(Iso)模拟局部交感神经张力增加，记录三层心肌的单相动作电位(MAP)，分析动作电位时程(APD)、图形特征和TDR的变化，观察室性心动过速(VT)的诱发情况和VT发作时的室壁激动顺序。
结果局部Iso的直接作用可降低三层心肌的APD，中层心肌细胞的APD降低更为明显使得TDR明显降低(31.8±2.1ms vs 22.6±3.3ms，P＜0.05)；诱发中层心肌细胞早期后除极(EAD)时TDR比无EAD时显著增加(41.0±2.2msvs 22.6±3.3ms，P＜0.05)；EAD多起源于中层心肌细胞且呈快频率依赖性，连续的EAD可触发VT；不同部位EAD诱发VT的室壁激动顺序不同，起源于中层心肌细胞的EAD触发VT时的室壁激动顺序为外层到中层最后激动内层心肌，起源于内层心肌细胞的EAD触发VT时的室壁激动顺序为内层到中层最后到外层心肌。
结论局部Iso的不均一性增加可引起有相互关联的心肌细胞自律性增加、EAD及TDR增加，易于在三层心肌之间形成折返，可能是其致室性心律失常的电生理学基础。
第三部分钠通道阻断剂对模拟在体犬LQT_3跨室壁复极离散度影响的实验研究
目的观察心率减慢时模拟在体犬长QT综合症第3型(LQT_3)动作电位时程(APD)和跨室壁复极离散度(TDR)的变化及钠通道阻断剂美西律(Mexiletine)对这种变化的影响，为先天性LQT_3窒性心律失常的防治提供实验依据。
方法采用自制电极同步记录在体犬左心室前壁跨室壁单相动作电位(MAP)，同时记录体表心电图，静脉注射海葵毒素(ATX-Ⅱ)模拟在体犬LQT_3，消融窦房结后通过改变心房起搏周长(PCL)控制心室率。分析用药前后三层心肌的APD、TDR和心电图形态的变化。
结果静脉注射ATX-Ⅱ(3μg／kg)后成功模拟出在体犬LQT_3模型，体表心电图表现为ST段明显延长，T波起始部位延迟出现，呈现不对称性高尖T波形态，与先天性LQT_3的心电图特点相似；PCL为500ms和1000ms时ATX-Ⅱ使TDR均显著性增加(分别为20±4 ms vs 41±9ms和39±5ms vs 83±10ms，P＜0.05)，但PCL为1000ms比500ms时TDR的增加幅度(△TDR)更为明显(44±13ms vs 20±12ms，P＜0.05)，伴随起源于中层心肌细胞的早期后除极和自发性室性心动过速发生；静脉注射Mexiletine(20μg／kg)能逆转ATX-Ⅱ的这种电生理作用。
结论LQT_3室性心律失常的发生呈慢心室率依赖性，Mexiletine可能对先天性LQT_3猝死的防治有一定的作用。
Part one Researches on Potassium Chloride Transmural Recording Electrode of Monophasic Action Potential with Local Administration of Agents
Objective: To design a kind of monophasic action potential(MAP)
recording electrode (KCl MAP electrode) which has the capability of agents administration locally, to steadily record the MAP of three myocardial layers synchronously; to probe into the methods of the electrode placement, the stability and duration of MAP recorded by the KCl MAP electrode; to probe into the feasibility of agents administration through the KCl MAP electrode; and to provide an ideal technique for the researches of transmural heterogeneity of repolarization and the mechanism of ventricular arrhythmia of canine in vivo.
Methords: The KCl MAP electrode with three pair of electrodes was made
up of 5F arterial sheath and insulated silver thread (0.2mm in diameter), the low melting point agarose gel containing 30% of potassium chloride was immitted into the core of the sheath. Transmural MAP of canine in vivo were recorded with the self-made KCl MAP electrode; the impact of local Isoprenaline on action potential duration(APD) of three layer myocardium, transmural dispersion of repolarization(TDR) and the inducing of ventricular arrhythmia were researched.
Results: Transmural MAP could be recorded by the KCl MAP electrode more than 120 minutes with the amplitude of action potential (APA) decreasing gradually but the analysis of the repolarization character not being affected. The APD of mid-myocardial (236.9±3.8ms vs 211.3±3.0ms) and TDR (35.7 ± 4.8 ms vs 24.9 ±3.9 ms) were decreased remarkably by Isoprenaline (10~(-5)mg/ml), Ventricular arrhythmia induced by early after-depolarization and triggered activity was prone to incurred at mid-myocardial.
Conclusion: It is an ideal method for the KCl MAP electrode to be applied
to the researches of transmural repolarization; TDR could be decreased by Isoprenaline and the mechanism of ventricular arrhythmia incurred by Isoprenaline is related to after-depolarization and triggered activity.
Part two
Electrophysiological Mechanism of Ventricular Arrhythmia Induced
by Local Isoprenaline in Situ
Objective To observe the electrophysiological phenomena incurred by the
administration of Isoprenaline(Iso) into canine left anterior ventricular wall in vivo and to probe into the mechanism of ventricular arrhythmia(VA) induced by the inhomogeneity increase of sympathetic nervous tension.
Methods The self-made potassium chloride monophasic action potential
recording electrodes (KCl MAP electrodes ) were pluged into the canine left anterior ventricular wall, where Iso was administered through the KCl MAP electrode to mimic the increase of local sympathetic nervous tension, monophasic action potentials (MAP) of the three layers (endocardium, midmyocardium and epicardium) at left anterior ventricular wall were recorded simultaneously before and after Iso been administered. The monophasic action potential duration (APD), the figure character of MAP , the transmural dispersion of repolarization (TDR) and the activation sequence of transmural anterior ventricular wall were analyzed.
Results The APD of all three layers could be decreased directly by Iso with
the TDR decreased remarkablely (31.8 ±2.1ms vs 22.6 ±3.3ms, P<0.05) , a significant increase of TDR (41.0±2.2ms vs 22.6±3.3ms, P<0.05) had been observed when EAD at midmyocardium been induced by Iso. The dependence of EAD on rapid ventricular frequency was observed, and VA could be triggered by consecutive EAD which mainly originated from midmyocardium. Different transmural activation sequence was observed when EAD originated from different layer of left anterior ventricular wall, the sequence was from epicardium to midmyocardium and then to endocardium when VT triggered by EAD originated from midmyocardium while the sequence was from endocardium to midmyocardium and then to epicardium when EAD originated from endocardium.
Conclusion The auto-rhythmicity, EAD and TDR could be increased
relatively by the inhomogeneity increase of Iso, when reentry was easily incurred between the three layer of myocardium, all these might be the electrophysiology bases of VA induced by local Iso.
Part three
Effects of Mexiletine on Transmural Dispersion of Repolarization of Left Anterior Ventricular Wall in Canine Model of LQT_3 in Vivo Objective To investigate the changes of action potential duration(APD) and transmural dispersion of repolarization(TDR) in canine model of long-QT syndrome type3(LQT_3) in vivo during bradycardia, to probe into the the impact of the sodium channel block-Mexiletine on this changes, and to provide experimental evidence for the prevention and treatment of ventricular arrhythmia in congenital LQT3.
Methords The monophasic action potential(MAP) of endocardium,
mid-myocardium and epicardium at the anterior ventricular wall were recorded synchronously in vivo by the self-made electrode, and the body surface electrocardiogram was recorded at the same time, Sea Anemone Toxin (ATX- Ⅱ) was administered intravenously to mimic LQT3 model, the heart rate was controlled by altering atrium pacing cycle length(PCL) after the sinoatrial node been ablated by 40% formaldehyde.
Results The LQT3 model had been made successfully by the intravenous
injection of ATX- Ⅱ (3 μg/kg). The TDR had been increased remarkably by the ATX-Ⅱ when the PCL was both 500ms and 1000ms (20 ±4 ms vs 41 ± 9ms and 39 ±5ms vs 83 ± 10ms, both P<0.05), but the net increase of TDR(ΔTDR) was more remarkable when the PCL was 1000ms compared with 500ms(44±13ms vs 20 ± 12ms, P<0.05), with the occurrence of early after depolarization(EAD) originated from mid-myocardium and spontaneity ventricular tachycardia. This kind of electrophysiological effect of ATX- Ⅱ could be reversed by Mexiletine(20μ g/kg).
Conclusion The occurrence of ventricular tachycardia in LQT_3 model is
bradycardia dependent, Mexiletine is probably an effective medicine in the prevention and treatment of the sudden cardiac death of congenital LQT_3.
引文
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