In vivo recording of adult zebrafish electrocardiogram and assessment of drug-induced QT prolongation
In vivo recording of adult zebrafish electrocardiogram and assessment of drug-induced QT prolongation
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DOI：
10.1152/ajpheart.00960.2005
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发表时间：
2006-07-01
影响因子：
4.8
通讯作者：
MacRae, Calum A.
中科院分区：
文献类型：
--
作者：
Milan, David J.;Jones, Ian L.;MacRae, Calum A.
在过去的十年中，斑马鱼已经成为研究发育和器官发生的主要模式生物。为了使这种生物的实验效用最大化，建立成体表型的方法将是重要的。我们之前提出，胚胎斑马鱼可能有助于高通量筛选药物诱导的心脏毒性。我们现在描述了一种可重复记录成年斑马鱼心电图的方法，并说明了其在延长心电图药物研究中的应用。通过在斑马鱼腹表皮插入两个针状电极获得了斑马鱼的脑电图。鱼被口服灌注，运动伪影被用麻痹剂量的muo - concontoxin GIIIB消除。试验化合物通过灌注系统输送。没有水合和氧合，这些鱼很快就会死亡。灌注系统的使用允许稳定记录bbbb6小时。基线传导间隔如下：PR， 66 ms (SD 14)；QRS, 34 ms (SD 11)；QT, 242 ms (SD 54)；R-R为398 ms （SD 77）。已知的QT延长剂阿司咪唑、氟哌啶醇、吡莫齐和特非那定分别导致校正QT增加18% （SD 9）、16% （SD 11）、17% （SD 9）和11% （SD 6）。对照药物可乐定、青霉素和心得安没有延长校正后的QT间期。总之，灌注和肌肉麻痹可以稳定、低噪音地记录斑马鱼的心电图。已知引起人类QT间期延长的药物在每种情况下都引起了鱼类QT间期延长。成熟斑马鱼表型分析的严格工具的开发将补充目前正在开发的用于胚胎和幼鱼的高通量分析。
In the last decade the zebrafish has become a major model organism for the study of development and organogenesis. To maximize the experimental utility of this organism, it will be important to establish methods for adult phenotyping. We previously proposed that the embryonic zebrafish may be useful in high-throughput screening for drug-induced cardio-toxicity. We now describe a method for the reproducible recording of the adult zebrafish ECG and illustrate its application in the investigation of QT-prolonging drugs. Zebrafish ECGs were obtained by inserting two needle electrodes through the ventral epidermis. Fish were perfused orally, and motion artifacts were eliminated with a paralytic dose of mu-conotoxin GIIIB. Test compounds were delivered via the perfusion system. Without a means of hydration and oxygenation, the fish succumb rapidly. The use of a perfusion system allowed stable recording for > 6 h. Baseline conduction intervals were as follows: PR, 66 ms (SD 14); QRS, 34 ms (SD 11); QT, 242 ms (SD 54); and R-R, 398 ms (SD 77). The known QT-prolonging agents astemizole, haloperidol, pimozide, and terfenadine caused corrected QT increases of 18% (SD 9), 16% (SD 11), 17% (SD 9), and 11% (SD 6), respectively. The control drugs clonidine, penicillin and propranolol did not prolong the corrected QT interval. In conclusion, perfusion and muscular paralysis allows stable, low-noise recording of zebrafish ECGs. Agents known to cause QT prolongation in humans caused QT prolongation in fish in each case. The development of rigorous tools for the phenotyping of adult zebrafish will complement the high-throughput assays currently under development for embryonic and larval fish.