Dog left ventricular midmyocardial myocytes for assessment of drug-induced delayed repolarization: short-term variability and proarrhythmic potential
Dog left ventricular midmyocardial myocytes for assessment of drug-induced delayed repolarization: short-term variability and proarrhythmic potential
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DOI：
10.1111/j.1476-5381.2009.00338.x
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发表时间：
2010-01-01
影响因子：
7.3
通讯作者：
Pollard, Chris E.
中科院分区：
文献类型：
--
作者：
Abi-Gerges, Najah;Valentin, Jean-Pierre;Pollard, Chris E.
背景和目的：评估新药延迟心室复极和致心律失常的可能性至关重要。我们研究了狗左心室中心肌细胞 (LVMM) 是否可以用作临床前模型来评估药物对动作电位持续时间 (APD) 的影响，以及在这些细胞中，短期变异性 (STV) 或三角测量是否可以预测致心律失常电位。实验方法：使用 Beagle LVMM 和浦肯野纤维 (PF) 记录 AP。评估六种参考药物对 50% (APD(50)) 和 90% (APD(90)) 复极、STV(APD)、三角测量（比率 APD(90)/APD(50)）以及 1 和 0.5 Hz 早期后除极 (EAD) 发生率的 APD 的影响。 主要结果：LVMM 提供稳定的 AP 记录，不受四次连续添加的影响 二甲亚砜。多非利特、d-索他洛尔、西沙必利、吡那地尔和地尔硫卓（而非特非那定）对 LVMM 中 APD 的影响与 PF 中记录的影响相当。 LVMM（而非 PF）对 I-Kr 阻滞剂表现出促心律失常反应。 EAD 的发生率与 AP 延长或三角测量的差异无关，但与复极的逐搏变异性相对应，此处量化为 APD 的 STV。结论和含义：LVMM 提供了合适的临床前模型来评估新药对 APD 的影响，并产生有关促心律失常的推定指标的附加信息，为综合 QT/TdP 风险评估增加价值。我们的研究结果支持这样的观点：STV(APD) 增加可以预测药物引起的致心律失常。英国药理学杂志 (2010) 159, 77-92; doi:10.1111/j.1476-5381.2009.00338.x； 2009 年 8 月 6 日在线发布
Background and purpose: Evaluation of the potential for delayed ventricular repolarization and proarrhythmia by new drugs is essential. We investigated if dog left ventricular midmyocardial myocytes (LVMMs) that can be used as a preclinical model to assess drug effects on action potential duration (APD) and whether in these cells, short-term variability (STV) or triangulation could predict proarrhythmic potential.Experimental approach: Beagle LVMMs and Purkinje fibres (PFs) were used to record APs. Effects of six reference drugs were assessed on APD at 50% (APD(50)) and 90% (APD(90)) of repolarization, STV(APD), triangulation (ratio APD(90)/APD(50)) and incidence of early afterdepolarizations (EADs) at 1 and 0.5 Hz.Key results: LVMMs provided stable recordings of AP, which were not affected by four sequential additions of dimethyl sulphoxide. Effects of dofetilide, d-sotalol, cisapride, pinacidil and diltiazem, but not of terfenadine, on APD in LVMMs were found to be comparable with those recorded in PFs. LVMMs, but not PFs, exhibited a proarrhythmic response to I-Kr blockers. Incidence of EADs was not related to differences in AP prolongation or triangulation, but corresponded to beat-to-beat variability of repolarization, here quantified as STV of APD.Conclusions and implications: LVMMs provide a suitable preclinical model to assess the effects of new drugs on APD and also yield additional information about putative indicators of proarrhythmia that add value to an integrated QT/TdP risk assessment. Our findings support the concept that increased STV(APD) may predict drug-induced proarrhythmia. British Journal of Pharmacology (2010) 159, 77-92; doi:10.1111/j.1476-5381.2009.00338.x; published online 6 August 2009