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

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.

Toxicity comparison of different active fractions extracted from radix Sophorae tonkinensis in zebrafish

“…Very recently, several studies regarding the use of zebrafish for hepatotoxicity and cardiovascular assessment were published from our group (He J.H. et al, 2013;Zhu et al, 2014;Shen et al, 2015). These and other studies strongly support the use of zebrafish for toxicity studies, including assessing and comparing the toxicity of Chinese herbs and their active fractions.…”

“…et al, 2013;Zhu et al, 2014;Shen et al, 2015). In the initial experiments, five testing concentrations ranging from 0.1, 1, 10, 100, and 1000 µg/ml were used for each sample and mortality was recorded daily.…”

“…At the end of the experiment, 15 zebrafish were randomly selected from each group for visual observation and image acquisition. Six specific phenotypic endpoints were validated and used in the cardiovascular toxicity analyses: heart rate, heart rhythm, pericardial edema, circulation, hemorrhage, and thrombosis as described in our earlier report (Zhu et al, 2014).…”

Do we damage nucleus pulposus tissue while treating cerebrovascular ischemic neurological deficits with nimodipine?

“…Predictive research projects are urgently needed to determine drugs with a potential to cause toxicity so that appropriate measures can be taken (1).…”

“…A cardiotoxicity study was performed on zebrafish that reported "nimodipine treatment resulted in atrial arrest with much slower but regular ventricular heart beating" (1). Pregnant rats were given 10 mg/kg/day during embryogenesis, and no detrimental effects were found (12,13).…”