A computational modelling approach combined with cellular electrophysiology data provides insights into the therapeutic benefit of targeting the late Na+ current.
A computational modelling approach combined with cellular electrophysiology data provides insights into the therapeutic benefit of targeting the late Na+ current.
复制标题
计算建模方法与细胞电生理学数据相结合，提供了对靶向晚 Na 电流的治疗益处的见解。
DOI：
10.1113/jphysiol.2014.279554
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Clancy,ColleenE
中科院分区：
文献类型：
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作者：
Yang,Pei-Chi;Song,Yejia;Giles,WayneR;Horvath,Balazs;Chen-Izu,Ye;Belardinelli,Luiz;Rajamani,Sridharan;Clancy,ColleenE
关键点心室动作电位平台期是一个高阻力阶段，这使得心室肌细胞容易受到小的电扰动。我们开发了一个基于计算的模型，用于GS-458967与心脏Na+通道的相互作用，通过记录豚鼠分离的单个心室肌细胞的实验数据，该模型预测GS-458967的治疗潜力主要来自设计的选择性抑制遗传性或获得性心律失常综合征患者的缓慢失活或晚期Na+电流（INaL）可通过降低心律失常触发因素的发生率和抑制心律失常促进心脏底物的一种成分（例如延长的不应期和动作电位时程的时空离散）来提供治疗益处。最近，研究了一种优先有效还原INaL的新型化合物GS-458967（阻断INaL的IC 50 = 130 nm）。GS-458967对内源性INaLin豚鼠心室肌细胞影响的实验测量结果表明，动作电位时程（APD）呈浓度依赖性显著降低。使用实验数据校准豚鼠心室动作电位Faber-Rudy计算模型中的INa和快速激活延迟整流K+电流IKr，我们模拟了GS-458967对豚鼠心室APD的影响。GS-458967（0.1 μm）在实验中引起28.67%的INa阻断和12.57%的APD缩短，而模型预测APD缩短10.06%，INaL阻断29.33%。INaL阻断的另一个作用是减少膜电位处于高电阻状态（即动作电位平台）的时间。为了验证靶向阻断INaL会使心室肌细胞对小电扰动不那么敏感的假设，我们使用计算模型来测试正常细胞和模拟长QT综合征细胞中小电扰动诱导的APD延长的程度。该模型预测，在存在GS-458967诱导的INaL阻滞的情况下，90%复极化变异性下的动作电位持续时间证明，对小电扰动的敏感性呈剂量依赖性显著降低。这种效应在遗传性长QT综合征的“疾病背景”中特别有效。使用实验和理论相结合的方法，我们的结果表明INaL阻断是一种有效的治疗策略。这是因为INaL的降低通过降低动作电位平台期的去极化电流来稳定动作电位波形。这减少了具有高膜电阻的动作电位的最脆弱阶段。总之，通过降低心肌基质对促进心律失常触发的小电扰动的敏感性，GS-458967等药物可能构成有效的抗心律失常药理学策略。
Key pointsThe ventricular action potential plateau is a phase of high resistance, which makes ventricular myocytes vulnerable to small electrical perturbations.We developed a computationally based model of GS‐458967 interaction with the cardiac Na+ channel, informed by experimental data recorded from guinea pig isolated single ventricular myocytes.The model predicts that the therapeutic potential of GS‐458967 derives largely from the designed property of significant potent selectivity for INaL.AbstractSelective inhibition of the slowly inactivating or late Na+current (INaL) in patients with inherited or acquired arrhythmia syndrome may confer therapeutic benefit by reducing the incidence of triggers for arrhythmia and suppressing one component of arrhythmia‐promoting cardiac substrates (e.g. prolonged refractoriness and spatiotemporal dispersion of action potential duration). Recently, a novel compound that preferentially and potently reducesINaL, GS‐458967 (IC50for block ofINaL= 130 nm) has been studied. Experimental measurements of the effects of GS‐458967 on endogenousINaLin guinea pig ventricular myocytes demonstrate a robust concentration‐dependent reduction in action potential duration (APD). Using experimental data to calibrateINaLand the rapidly activating delayed rectifier K+current,IKr, in the Faber–Rudy computationally based model of the guinea pig ventricular action potential, we simulated effects of GS‐458967 on guinea pig ventricular APD. GS‐458967 (0.1 μm) caused a 28.67% block ofINaLand 12.57% APD shortening in experiments, while the model predicted 10.06% APD shortening with 29.33% block ofINaL. An additional effect ofINaLblock is to reduce the time during which the membrane potential is in a high resistance state (i.e. the action potential plateau). To test the hypothesis that targeted block ofINaLwould make ventricular myocytes less susceptible to small electrical perturbations, we used the computational model to test the degree of APD prolongation induced by small electrical perturbations in normal cells and in cells with simulated long QT syndrome. The model predicted a substantial dose‐dependent reduction in sensitivity to small electrical perturbations as evidenced by action potential duration at 90% repolarization variability in the presence of GS‐458967‐inducedINaLblock. This effect was especially potent in the ‘disease setting’ of inherited long QT syndrome. Using a combined experimental and theoretical approach, our results suggest thatINaLblock is a potent therapeutic strategy. This is because reduction ofINaLstabilizes the action potential waveform by reducing depolarizing current during the plateau phase of the action potential. This reduces the most vulnerable phase of the action potential with high membrane resistance. In summary, by reducing the sensitivity of the myocardial substrate to small electrical perturbations that promote arrhythmia triggers, agents such as GS‐458967 may constitute an effective antiarrhythmic pharmacological strategy.