Department of Biopharmacy, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland; Independent Laboratory of Behavioral Studies, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland.
Department of Biopharmacy, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland.
Toxicol Appl Pharmacol. 2022 Jan 1;434:115812. doi: 10.1016/j.taap.2021.115812. Epub 2021 Nov 26.
Cardiovascular toxicity represents one of the most common reasons for clinical trial failure. Consequently, early identification of novel cardioprotective strategies could prevent the later-stage drug-induced cardiac side effects. The use of zebrafish (Danio rerio) in preclinical studies has greatly increased. High-throughput and low-cost of assays make zebrafish model ideal for initial drug discovery. A common strategy to induce heart failure is a chronic β-adrenergic (βAR) stimulation. Herein, we set out to test a panel of βAR agonists to develop a pharmacological heart failure model in zebrafish. We assessed βAR agonists with respect to the elicited mortality, changes in heart rate, and morphological alterations in zebrafish larvae according to Fish Embryo Acute Toxicity Test. Among the tested βAR agonists, epinephrine elicited the most potent onset of heart stimulation (EC = 0.05 mM), which corresponds with its physiological role as catecholamine. However, when used at ten-fold higher dose (0.5 mM), the same compound caused severe heart rate inhibition (-28.70 beats/min), which can be attributed to its cardiotoxicity. Further studies revealed that isoetharine abolished body pigmentation at the sublethal dose of 7.50 mM. Additionally, as a proof of concept that zebrafish can mimic human cardiac physiology, we tested βAR antagonists (propranolol, carvedilol, metoprolol, and labetalol) and verified that they inhibited fish heart rate in a similar fashion as in humans. In conclusion, we proposed two novel pharmacological models in zebrafish; i.e., epinephrine-dependent heart failure and isoetharine-dependent transparent zebrafish. We provided strong evidence that the zebrafish model constitutes a valuable tool for cardiovascular research.
心血管毒性是临床试验失败的最常见原因之一。因此，早期识别新的心脏保护策略可以预防后期药物引起的心脏副作用。斑马鱼（Danio rerio）在临床前研究中的应用大大增加。高通量和低成本的测定方法使斑马鱼模型成为初始药物发现的理想选择。诱导心力衰竭的一种常见策略是慢性β-肾上腺素能（βAR）刺激。在此，我们着手测试一组βAR 激动剂，以在斑马鱼中开发一种药理学心力衰竭模型。我们根据鱼类胚胎急性毒性试验，评估了βAR 激动剂对诱发死亡率、心率变化和斑马鱼幼虫形态改变的影响。在所测试的βAR 激动剂中，肾上腺素引起的心脏刺激作用最强（EC=0.05mM），这与其作为儿茶酚胺的生理作用相对应。然而，当使用十倍高剂量（0.5mM）时，相同的化合物会导致严重的心率抑制（-28.70 次/分钟），这可归因于其心脏毒性。进一步的研究表明，异他林在亚致死剂量 7.50mM 时消除了身体色素沉着。此外，作为斑马鱼可以模拟人类心脏生理学的概念验证，我们测试了βAR 拮抗剂（普萘洛尔、卡维地洛、美托洛尔和拉贝洛尔），并验证了它们以类似于人类的方式抑制鱼类心率。总之，我们在斑马鱼中提出了两种新的药理学模型；即肾上腺素依赖性心力衰竭和异他林依赖性透明斑马鱼。我们提供了强有力的证据表明，斑马鱼模型是心血管研究的有价值工具。
