I_（Na，L）导致SAN功能紊乱和心内传导障碍
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摘要
大多数心脏上的电压门控钠通道在细胞除极几毫秒内短暂开放，形成动作电位上升支。但是一些通道在几百毫秒后，动作电位的平台期仍然开放，形成持续性钠电流，又称晚钠电流(I_(Na，L))。I_(Na，L)增加可导致许多疾病，如长QT间期综合症(LQTS)的第3型(LQT3)。患者可因心室复极延迟，QT间期延长而导致严重室性心律失常。但是I_(Na，L)增大对窦房结和心脏传导系统的影响研究不多。本实验主要研究I_(Na，L)对LQT3小鼠模型中窦房结功能和心内传导系统的影响。研究发现I_(Na，L)可以导致LQT3小鼠模型的窦房结功能紊乱和心内传导障碍。而I_(Na，L)抑制剂雷诺嗪对海葵毒素Ⅱ(ATX-Ⅱ)诱导的LQT3小鼠离体心脏水平上对窦房结功能紊乱和室性心律失常具有一定的疗效。
第一部分ATX-Ⅱ诱导的小鼠LQT3模型出现窦房结功能紊乱和心内传导障碍及雷诺嗪的拮抗作用
目的：分别应用海葵毒素Ⅱ(ATX-Ⅱ)和雷诺嗪增强或抑制晚钠电流(I_(Na，L))，来证明I_(Na，L)致小鼠窦性心律失常和传导障碍作用。
方法：实验采用不同浓度海葵毒素Ⅱ(ATX-Ⅱ)灌流小鼠离体心脏，构建LQT3模型。记录心电图(ECG)和单相动作电位(MAP)，并与加用雷诺嗪后结果比较。并进行窦房结(sinoatrial node，SAN)组织标测研究以上药物对窦房结起搏和传导的影响。
结果：研究发现1-10 nM ATX-Ⅱ灌流离体心脏后，小鼠心率明显减慢；PR间期，QT间期和QTc延长；单相动作电位时程(MAPD)，窦房结恢复时间(SNRT)和校正的窦房结恢复时间(CSNRT)延长；早期后除极(EAD)和延迟后除极(DAD)明显增加并伴反复出现的室性心动过速(VT)和窦房缓慢型心律失常。窦房结组织标测发现ATX-Ⅱ减缓窦房结起搏和传导。ATX-Ⅱ的以上作用可被10μM雷诺嗪明显缓解。
结论：ATX-Ⅱ作为I_(Na，L)增强剂可导致小鼠窦性心律失常和传导障碍，而I_(Na，L)阻断剂雷诺嗪则明显缓解以上心律失常。
第二部分转基因LQT3小鼠模型出现窦房结功能紊乱和心内传导障碍
目的：本研究利用转基因LQT3小鼠模型，验证Scn5a+／Δ小鼠易发生室性心律失常并观察窦房结和传导功能
方法：利用转基因LQT3小鼠模型，记录体表心电图并行食道电刺激以统计心律失常事件。并行窦房结组织水平标测研究窦房结起搏传导功能。
结果：除QT间期和QTc延长，Scn5a+／Δ小鼠出现明显的窦房结(sinoatrial node，SAN)功能紊乱。尽管基础状态ECG显示Scn5a+／Δ和野生型(WT)小鼠的心律失常发生率没有差别，但经程序电刺激(PES)后Scn5a+／Δ小鼠出现窦性心动过缓(sinusbradycardia，SB)，窦性停博(sinus pause)或窦性间歇(sinus arrest)。窦房结组织水平Scn5a+／Δ小鼠起搏频率明显慢于WT小鼠。而且Scn5a+／Δ小鼠的窦房结恢复时间(SNRT)和校正的窦房结恢复时间(CSNRT)更长。小鼠整体水平研究还发现Scn5a+／Δ小鼠ECG出现PR间期和QRS波延长，以及Ⅱ-Ⅲ度房室传导阻滞。窦房结组织水平研究发现Scn5a+／Δ小鼠窦房结的兴奋向房间隔(septum，SEPT)和下腔静脉(inferior vena cava，IVC)方向传导明显减慢。
结论：研究证实Scn5a+／Δ小鼠存在SAN功能降低，心内传导障碍。
The late sodium current (I_(Na,L))is a sustained component of the fast Na~+ current Asrecently appreciated,lots of cardiac diseases including the LQT3 are associated withabnormal INa,L enhancement.We hypothesized that an increase of I_(Na,L) may induce notonly prolonged QT and ventricular arrhythmia but also play a critical role in thepathophysiology of sinus node dysfunction and depressed intraventricular conductionin the LQT3.Anemone toxinⅡ(ATX-Ⅱ) (1-10 nmol/l) was used to enhance I_(Na,L) whileranolazine (10μm) was applied to block ATX-Ⅱ-induced I_(Na,L).Scn5a+/△transgenicmice were also used to verification our hypothesis.The data reveal that an increase ofI_(Na,L) induced the alterations in sinus node function and intracardiac conduction andpharmacological modulation of ranolazine may be the therapeutic potential.
PartⅠSinus Node Dysfunction and Intracardiac Conduction ina Murine Model of Long QT Syndrome Type 3 Induced byATX-Ⅱand Rescue Effect of Ranolazine
Object:The aim of this study was to characterize the role of the late Na~+ current (I_(Na,L)) as amechanism for induction of both tachy- and brady-arrhythmias in murine heart andsino-atrial node tissue.
Method:The sea anemone toxin ATX-Ⅱand ranolazine were used to evoke and block,respectively,I_(Na,L).
Result:In sixteen hearts studied,exposure to 1 to 10 nM ATX-Ⅱcaused a slowing ofintrinsic heart rate and prolongations of the PR and QT intervals,the duration of themonophasic action potential,and the sinus node recovery time,accompanied by frequentoccurrences of early afterdepolarisations,delayed afterdepolarisations and rapid,repetitiveventricular tachycardiac and sino-atrial bradycardic arrhythmias.ATX-Ⅱalso slowed sinusnode pacemaking,and induced bradycardic arrhythmias in isolated sino-atrial preparations(n=5).The ATX-II-induced alteration of electrophysiological properties and occurrence ofarrhythmic events were significantly attenuated by 10μM ranolazine in intact hearts (n=11)and isolated sino-atrial preparations (n=5).
Conclusion:The I_(Na,L) enhancer ATX-Ⅱcauses both tachy- and brady-arrhythmias in themurine heart,and these arrhythmias are markedly attenuated by the I_(Na,L) blocker,ranolazine(10μM).The results suggest that I_(Na,L) blockade may be the mechanism underlying thereductions of both brady- and tachy-arrhythmias by ranolazine that were observed duringthe MERLIN-TIMI clinical outcomes trial.
PartⅡSinus Node Function and Intracardiac Conduction ina Murine Model of Long QT Syndrome Type 3
Object:The aim of this study was to characterize the role of the late Na~+ current (I_(Na,L)) as amechanism for induction of both tachy- and brady-arrhythmias in murine heart andsino-atrial node tissue.
Method:Scn5a +/△transgenic mice were used to verification our hypothesis.
Result:The present experiments on an established murine,Scn5a+/△,model for LQT3extended previous reports of its ventricular arrhythmogenic properties.In addition tosignificant prolongations in QT and QTc intervals in common with human LQT3,Scn5a+/△mice showed evidence for significant sino-atrial node (SAN) dysfunction.Although baseline electrocardiographic heart rates in intact Scn5a+/△preparations wereindistinguishable from WT,anaesthetised Scn5a+/△mice showed episodes of sinusbradycardia,sinus pause or arrest.Isolated Scn5a +/△sino-atrial preparations showed lowermean intrinsic heart rates.Furthermore,Scn5a +/△mice showed a significant longer SNRTfollowing burst pacing.Both intact animals and isolated Scn5a+/△sino-atrial preparationsshowed evidence for depressed intra-atrial,atrioventricular node and intraventricularconduction in the Scn5a +/△in the absence of significant sino-atrial exit block.Conclusion:Thus electrocardiographic studies demonstrated episodes of second and thirddegree heart block,as well as prolonged PR intervals and QRS durations in Scn5a+/△.Multi-array electrode mapping studies demonstrated significantly greater latencies inconduction of excitation between SA node,and septum and inferior vena cava,but not theright atrium and superior vena cava in isolated Scn5a +/△sino-atrial preparations Togetherthese findings demonstrate alterations in sinus node function and intracardiac conductionthereby recapitulating phenotypic characteristics reported in the corresponding clinicalcondition.
第一部分ATX-Ⅱ诱导的小鼠LQT3模型出现窦房结功能紊乱和心内传导障碍及雷诺嗪的拮抗作用
目的：分别应用海葵毒素Ⅱ(ATX-Ⅱ)和雷诺嗪增强或抑制晚钠电流(I_(Na，L))，来证明I_(Na，L)致小鼠窦性心律失常和传导障碍作用。
方法：实验采用不同浓度海葵毒素Ⅱ(ATX-Ⅱ)灌流小鼠离体心脏，构建LQT3模型。记录心电图(ECG)和单相动作电位(MAP)，并与加用雷诺嗪后结果比较。并进行窦房结(sinoatrial node，SAN)组织标测研究以上药物对窦房结起搏和传导的影响。
结果：研究发现1-10 nM ATX-Ⅱ灌流离体心脏后，小鼠心率明显减慢；PR间期，QT间期和QTc延长；单相动作电位时程(MAPD)，窦房结恢复时间(SNRT)和校正的窦房结恢复时间(CSNRT)延长；早期后除极(EAD)和延迟后除极(DAD)明显增加并伴反复出现的室性心动过速(VT)和窦房缓慢型心律失常。窦房结组织标测发现ATX-Ⅱ减缓窦房结起搏和传导。ATX-Ⅱ的以上作用可被10μM雷诺嗪明显缓解。
结论：ATX-Ⅱ作为I_(Na，L)增强剂可导致小鼠窦性心律失常和传导障碍，而I_(Na，L)阻断剂雷诺嗪则明显缓解以上心律失常。
第二部分转基因LQT3小鼠模型出现窦房结功能紊乱和心内传导障碍
目的：本研究利用转基因LQT3小鼠模型，验证Scn5a+／Δ小鼠易发生室性心律失常并观察窦房结和传导功能
方法：利用转基因LQT3小鼠模型，记录体表心电图并行食道电刺激以统计心律失常事件。并行窦房结组织水平标测研究窦房结起搏传导功能。
结果：除QT间期和QTc延长，Scn5a+／Δ小鼠出现明显的窦房结(sinoatrial node，SAN)功能紊乱。尽管基础状态ECG显示Scn5a+／Δ和野生型(WT)小鼠的心律失常发生率没有差别，但经程序电刺激(PES)后Scn5a+／Δ小鼠出现窦性心动过缓(sinusbradycardia，SB)，窦性停博(sinus pause)或窦性间歇(sinus arrest)。窦房结组织水平Scn5a+／Δ小鼠起搏频率明显慢于WT小鼠。而且Scn5a+／Δ小鼠的窦房结恢复时间(SNRT)和校正的窦房结恢复时间(CSNRT)更长。小鼠整体水平研究还发现Scn5a+／Δ小鼠ECG出现PR间期和QRS波延长，以及Ⅱ-Ⅲ度房室传导阻滞。窦房结组织水平研究发现Scn5a+／Δ小鼠窦房结的兴奋向房间隔(septum，SEPT)和下腔静脉(inferior vena cava，IVC)方向传导明显减慢。
结论：研究证实Scn5a+／Δ小鼠存在SAN功能降低，心内传导障碍。
The late sodium current (I_(Na,L))is a sustained component of the fast Na~+ current Asrecently appreciated,lots of cardiac diseases including the LQT3 are associated withabnormal INa,L enhancement.We hypothesized that an increase of I_(Na,L) may induce notonly prolonged QT and ventricular arrhythmia but also play a critical role in thepathophysiology of sinus node dysfunction and depressed intraventricular conductionin the LQT3.Anemone toxinⅡ(ATX-Ⅱ) (1-10 nmol/l) was used to enhance I_(Na,L) whileranolazine (10μm) was applied to block ATX-Ⅱ-induced I_(Na,L).Scn5a+/△transgenicmice were also used to verification our hypothesis.The data reveal that an increase ofI_(Na,L) induced the alterations in sinus node function and intracardiac conduction andpharmacological modulation of ranolazine may be the therapeutic potential.
PartⅠSinus Node Dysfunction and Intracardiac Conduction ina Murine Model of Long QT Syndrome Type 3 Induced byATX-Ⅱand Rescue Effect of Ranolazine
Object:The aim of this study was to characterize the role of the late Na~+ current (I_(Na,L)) as amechanism for induction of both tachy- and brady-arrhythmias in murine heart andsino-atrial node tissue.
Method:The sea anemone toxin ATX-Ⅱand ranolazine were used to evoke and block,respectively,I_(Na,L).
Result:In sixteen hearts studied,exposure to 1 to 10 nM ATX-Ⅱcaused a slowing ofintrinsic heart rate and prolongations of the PR and QT intervals,the duration of themonophasic action potential,and the sinus node recovery time,accompanied by frequentoccurrences of early afterdepolarisations,delayed afterdepolarisations and rapid,repetitiveventricular tachycardiac and sino-atrial bradycardic arrhythmias.ATX-Ⅱalso slowed sinusnode pacemaking,and induced bradycardic arrhythmias in isolated sino-atrial preparations(n=5).The ATX-II-induced alteration of electrophysiological properties and occurrence ofarrhythmic events were significantly attenuated by 10μM ranolazine in intact hearts (n=11)and isolated sino-atrial preparations (n=5).
Conclusion:The I_(Na,L) enhancer ATX-Ⅱcauses both tachy- and brady-arrhythmias in themurine heart,and these arrhythmias are markedly attenuated by the I_(Na,L) blocker,ranolazine(10μM).The results suggest that I_(Na,L) blockade may be the mechanism underlying thereductions of both brady- and tachy-arrhythmias by ranolazine that were observed duringthe MERLIN-TIMI clinical outcomes trial.
PartⅡSinus Node Function and Intracardiac Conduction ina Murine Model of Long QT Syndrome Type 3
Object:The aim of this study was to characterize the role of the late Na~+ current (I_(Na,L)) as amechanism for induction of both tachy- and brady-arrhythmias in murine heart andsino-atrial node tissue.
Method:Scn5a +/△transgenic mice were used to verification our hypothesis.
Result:The present experiments on an established murine,Scn5a+/△,model for LQT3extended previous reports of its ventricular arrhythmogenic properties.In addition tosignificant prolongations in QT and QTc intervals in common with human LQT3,Scn5a+/△mice showed evidence for significant sino-atrial node (SAN) dysfunction.Although baseline electrocardiographic heart rates in intact Scn5a+/△preparations wereindistinguishable from WT,anaesthetised Scn5a+/△mice showed episodes of sinusbradycardia,sinus pause or arrest.Isolated Scn5a +/△sino-atrial preparations showed lowermean intrinsic heart rates.Furthermore,Scn5a +/△mice showed a significant longer SNRTfollowing burst pacing.Both intact animals and isolated Scn5a+/△sino-atrial preparationsshowed evidence for depressed intra-atrial,atrioventricular node and intraventricularconduction in the Scn5a +/△in the absence of significant sino-atrial exit block.Conclusion:Thus electrocardiographic studies demonstrated episodes of second and thirddegree heart block,as well as prolonged PR intervals and QRS durations in Scn5a+/△.Multi-array electrode mapping studies demonstrated significantly greater latencies inconduction of excitation between SA node,and septum and inferior vena cava,but not theright atrium and superior vena cava in isolated Scn5a +/△sino-atrial preparations Togetherthese findings demonstrate alterations in sinus node function and intracardiac conductionthereby recapitulating phenotypic characteristics reported in the corresponding clinicalcondition.
引文
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