Evaluation of O-adrenergic ligands for development of pharmacological heart failure and transparency models in zebrafish

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 O-adrenergic (OAR) stimulation. Herein, we set out to test a panel of OAR agonists to develop a pharmacological heart failure model in zebrafish. We assessed OAR 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 OAR agonists, epinephrine elicited the most potent onset of heart stimulation (EC50 = 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 OAR 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.

Automated summary

Cardiovascular toxicity is a common reason for clinical trial failure, and early identification of cardioprotective strategies is crucial. The use of zebrafish as a model in preclinical studies has great potential in drug discovery. This study established two novel pharmacological models of heart failure in zebrafish using OAR agonists and evaluated their effects on mortality, heart rate, and morphology. The results demonstrate the value of zebrafish as a tool for cardiovascular research and its ability to mimic human cardiac physiology.