Human cardiotoxic drugs delivered by soaking and microinjection induce cardiovascular toxicity in zebrafish

Authors

  • Jun-Jing Zhu,

    1. Hunter Biotechnology, Inc., Hangzhou, Zhejiang Province, China
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  • Yi-Qiao Xu,

    1. Hunter Biotechnology, Inc., Hangzhou, Zhejiang Province, China
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  • Jian-Hui He,

    1. Hunter Biotechnology, Inc., Hangzhou, Zhejiang Province, China
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  • Hang-Ping Yu,

    1. Hunter Biotechnology, Inc., Hangzhou, Zhejiang Province, China
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  • Chang-Jiang Huang,

    1. Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, Wenzhou Medical College, Wenzhou, Zhejiang Province, China
    2. Institute of Watershed Science and Environmental Ecology, Wenzhou Medical College, Wenzhou, Zhejiang Province, China
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  • Ji-Min Gao,

    1. Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, Wenzhou Medical College, Wenzhou, Zhejiang Province, China
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  • Qiao-Xiang Dong,

    1. Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, Wenzhou Medical College, Wenzhou, Zhejiang Province, China
    2. Institute of Watershed Science and Environmental Ecology, Wenzhou Medical College, Wenzhou, Zhejiang Province, China
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  • Yao-Xian Xuan,

    Corresponding author
    1. Center of Safety Evaluation, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang Province, China
    • Correspondence to: C.-Q. Li, Hunter Biotechnology, Inc., Transfarland, Hangzhou, Zhejiang Province 311231, China.

      E-mail: chunqili@wzmc.edu.cn

      Y.-X. Xuan, Center of Safety Evaluation, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang Province 310013, China.

      E-mail: nndsvc@mail.hz.zj.cn

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  • Chun-Qi Li

    Corresponding author
    1. Hunter Biotechnology, Inc., Hangzhou, Zhejiang Province, China
    2. Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, Wenzhou Medical College, Wenzhou, Zhejiang Province, China
    3. Institute of Watershed Science and Environmental Ecology, Wenzhou Medical College, Wenzhou, Zhejiang Province, China
    • Correspondence to: C.-Q. Li, Hunter Biotechnology, Inc., Transfarland, Hangzhou, Zhejiang Province 311231, China.

      E-mail: chunqili@wzmc.edu.cn

      Y.-X. Xuan, Center of Safety Evaluation, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang Province 310013, China.

      E-mail: nndsvc@mail.hz.zj.cn

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ABSTRACT

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 24 h 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. Copyright © 2013 John Wiley & Sons, Ltd.

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