Cardiac physiological changes induced by cardiovascular drugs from different chemical classes in zebrafish mirrored in mice: A predictive tool for comprehensive risk assessment.

Abstract

Objective: Our study investigated the impact of various cardiovascular drug on the cardiac physiology of zebrafish embryos and validated these findings in mice.

Background: Cardiotoxicity has significantly contributed to the high drug attrition rate over the last two decades, underscoring the cardiac risk assessment in drug discovery and development. Although regulatory authority's guidelines specified the cell-based assays for the safety assessment of drugs, the current requirements fall short due to a lack of in vivo biology. The use of zebrafish experimental system has surged in developmental and pathophysiological investigation due to their striking resemblance to mammals. Hence, we used the zebrafish model system for cardiovascular drug studies and validated it in the mice model.

Materials and methods: The zebrafish embryos of 72 hours post-fertilization (hpf) were exposed to different CVS drug and, recorded their heart rate, and further validated in mice.

Results: We observed that exposure to amlodipine (a calcium channel blocker), atenolol (a class II antiarrhythmic), and amiodarone (a class III antiarrhythmic) led to dose-dependent reductions in heart rate in zebrafish embryos, with effects varying based on drug concentration and mechanism of action. Specifically, amiodarone treatment resulted in a dose-dependent decrease in heart rate (0.001-100 μM) and atrioventricular block starting at a 10 μM concentration. Each class of cardiovascular drug demonstrated unique cardiac effects in zebrafish embryos, reflecting similar patterns in mice treated with these drugs.

Conclusions: Our findings highlight the zebrafish model's utility for early-phase cardiac risk assessment in drug discovery due to its high throughput capabilities and other beneficial features.