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首页> 外文期刊>Journal of applied toxicology >Human cardiotoxic drugs delivered by soaking and microinjection induce cardiovascular toxicity in zebrafish
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Human cardiotoxic drugs delivered by soaking and microinjection induce cardiovascular toxicity in zebrafish

机译：通过浸泡和显微注射递送的人类心脏毒性药物可诱发斑马鱼的心血管毒性

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摘要

Cardiovascular toxicity is a major challenge for the pharmaceutical industry and predictive screening models to identify and eliminate pharmaceuticals with the potential to cause cardiovascular toxicity in humans are urgently needed. In this study, taking advantage of the transparency of larval zebrafish, Danio rerio, we assessed cardiovascular toxicity of seven known human cardiotoxic drugs (aspirin, clomipramine hydrochloride, cyclophosphamide, nimodipine, quinidine, terfenadine and verapamil hydrochloride) and two non-cardiovascular toxicity drugs (gentamicin sulphate and tetracycline hydrochloride) in zebrafish using six specific phenotypic endpoints: heart rate, heart rhythm, pericardial edema, circulation, hemorrhage and thrombosis. All the tested drugs were delivered into zebrafish by direct soaking and yolk sac microinjection, respectively, and cardiovascular toxicity was quantitatively or qualitatively assessed at 4 and 24h post drug treatment. The results showed that aspirin accelerated the zebrafish heart rate (tachycardia), whereas clomipramine hydrochloride, cyclophosphamide, nimodipine, quinidine, terfenadine and verapamil hydrochloride induced bradycardia. Quinidine and terfenadine also caused atrioventricular (AV) block. Nimodipine treatment resulted in atrial arrest with much slower but regular ventricular heart beating. All the tested human cardiotoxic drugs also induced pericardial edema and circulatory disturbance in zebrafish. There was no sign of cardiovascular toxicity in zebrafish treated with non-cardiotoxic drugs gentamicin sulphate and tetracycline hydrochloride. The overall prediction success rate for cardiotoxic drugs and non-cardiotoxic drugs in zebrafish were 100% (9/9) as compared with human results, suggesting that zebrafish is an excellent animal model for rapid in vivo cardiovascular toxicity screening. The procedures we developed in this report for assessing cardiovascular toxicity in zebrafish were suitable for drugs delivered by either soaking or microinjection.
机译：心血管毒性是制药业的主要挑战，因此迫切需要一种预测性筛选模型，以鉴定和消除可能对人造成心血管毒性的药物。在这项研究中，我们利用斑马鱼幼体斑马鱼Danio rerio的透明性，评估了七种已知的人类心脏毒性药物（阿司匹林，盐酸氯米帕明，环磷酰胺，尼莫地平，奎尼丁，特非那定和盐酸维拉帕米）的心血管毒性和两种非心血管毒性药物（硫酸庆大霉素和盐酸盐四环素）在斑马鱼中使用六个特定的表型终点：心率，心律，心包水肿，循环，出血和血栓形成。分别通过直接浸泡和卵黄囊显微注射将所有测试药物分别递送到斑马鱼中，并在药物治疗后4小时和24小时对心血管毒性进行定量或定性评估。结果表明，阿司匹林可加速斑马鱼的心律（心动过速），而盐酸氯米帕明，环磷酰胺，尼莫地平，奎尼丁，特非那定和盐酸维拉帕米可引起心动过缓。奎尼丁和特非那定也引起房室（AV）阻滞。尼莫地平治疗导致心房骤停，但心律跳动慢得多，但规律。所有测试过的人类心脏毒性药物均会引起斑马鱼心包水肿和循环障碍。用非庆大霉素硫酸庆大霉素和盐酸四环素治疗的斑马鱼没有心血管毒性的迹象。与人类结果相比，斑马鱼中心脏毒性药物和非心脏毒性药物的总体预测成功率为100％（9/9），这表明斑马鱼是用于快速体内心血管毒性筛选的出色动物模型。我们在本报告中开发的评估斑马鱼心血管毒性的程序适用于通过浸泡或显微注射递送的药物。

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