Cardiac tissue slices with prolonged survival for in vitro drug safety screening
Cardiac tissue slices with prolonged survival for in vitro drug safety screening
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DOI：
10.1016/j.vascn.2011.12.002
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发表时间：
2012-09-01
影响因子：
1.9
通讯作者：
Lohmann, Horst
中科院分区：
文献类型：
--
作者：
Bussek, Alexandra;Schmidt, Matthias;Lohmann, Horst
引言：我们最近介绍了使用哺乳动物心脏组织切片进行体外药物试验。在这里，我们展示了如何这种方法可以应用于长期的研究，在安全pharmacology.Methods：在新鲜制备的豚鼠或大鼠心室的心脏切片，细胞外场电位（FP）和细胞内动作电位（AP）记录在响应电刺激使用4通道心脏切片筛选系统“同步切片”。为了评估连续几天后制备的切片的活力，FP/AP参数，如持续时间和潜伏期的药物效应，monitored.Results：在存在的钾通道阻滞剂E4031（1 μ M），FP和AP持续时间（FPD和APD）显着增加（FPD，39.0%; APD，28.1%）在豚鼠心室片。切片制备后24-28 h观察到类似变化（FPD，48.6%; APD，25.4%）。此外，在钙通道阻滞剂硝苯地平（10 μ M）的存在下，AP持续时间在制备当天（40.5%）和24-28小时后（38.7%）减少。与此相反，在钾通道阻断剂4-氨基吡啶（30 mM）的存在下，AP持续时间延长4.95和4.19倍，2-8小时和24- 2 - 8小时后，分别制备。最后，FP传播被差距连接阻断剂甘珀酸（30 μ M）反复减慢，如连续三天观察到的FP起始潜伏期增加所揭示的（制备后2-8 h，93.0%; 24- 2 - 8 h，76.8%，48-56 h，61.7%）。新鲜分离的心脏切片再现了制备后超过24小时的生理和药理学反应。因此，心脏切片可以在制备后使用数天，这使得它们成为用于电生理学研究的稳健模型。我们建议心脏切片可以成为心脏研究和药物风险评估的通用工具。(C)2011 Elsevier Inc. All rights reserved.
Introduction: We have recently introduced the use of mammalian cardiac tissue slices for in vitro drug testing purposes. Here we show how this method can be applied for long-term studies in safety pharmacology.Methods: In freshly prepared cardiac slices from guinea-pig or rat ventricle, extracellular field potentials (FP) and intracellular action potentials (AP) were recorded in response to electrical stimulation using the 4-channel heart slice screening system 'Synchroslice'. To assess viability of the slices on consecutive days after preparation, drug effects on FP/AP parameters, like duration and latency, were monitored.Results: In the presence of the potassium channel blocker E4031 (1 mu M), FP and AP duration (FPD and APD) were significantly increased (FPD, 39.0%; APD, 28.1%) in guinea-pig ventricular slices. Similar changes were observed 24-28 h after slice preparation (FPD, 48.6%; APD, 25.4%). Furthermore, AP duration was reduced in the presence of the calcium channel blocker nifedipine (10 mu M) on the day of preparation (40.5%) and 24-28 h later (38.7%). In contrast, in the presence of the potassium channel blocker 4-aminopyridine (30 mM) AP duration was prolonged 4.95 and 4.19-fold, 2-8 h and 24-28 h after preparation, respectively. Finally, FP propagation was repeatedly slowed down by the gap junction blocker carbenoxolone (30 mu M), as revealed from FP onset latency increases observed on three consecutive days (2-8 h after preparation, 93.0%; 24-28 h, 76.8%, 48-56 h, 61.7%).Discussion: Freshly isolated cardiac slices reproduced established physiological and pharmacological responses for more than 24 h after preparation. Thus, cardiac slices can be used for several days after preparation which makes them a robust model for electrophysiological studies. We propose that cardiac slices can become a versatile tool in heart research and risk assessment of drugs. (C) 2011 Elsevier Inc. All rights reserved.