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Effects of bepridil on early cardiac development of zebrafish
Ya-Lan Wei1,2,3, Yu-Qing Lei1,2, Zhou-Jie Ye1,2,3
1NHC Key Laboratory of Technical Evaluation of Fertility Regulation for Non-Human Primate, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, 350013, China.
Insights
Bepridil causes significant toxicity in developing embryos, leading to heart and liver abnormalities. This study highlights potential risks of bepridil use during pregnancy, impacting fetal cardiac development.
Area of Science:
- Cardiovascular Pharmacology
- Developmental Toxicology
- Molecular Biology
Background:
- Bepridil is a calcium channel blocker used for arrhythmia and heart failure.
- Its long half-life and complex pharmacology necessitate further investigation.
- Potential toxicity and effects on embryonic development are largely unknown.
Purpose of the Study:
- To investigate the toxicity of bepridil on rat myocardial H9c2 cells.
- To evaluate the effects of bepridil on zebrafish embryonic development.
- To understand the molecular mechanisms underlying bepridil-induced developmental toxicity.
Main Methods:
- In vitro studies using rat myocardial H9c2 cells.
- Zebrafish embryo models for in vivo toxicity assessment.
- RNA-sequencing (RNA-seq) for gene expression profiling.
Main Results:
- Bepridil induced calcium overload, cytoplasmic vacuolization, and nuclear abnormalities in H9c2 cells.
- Zebrafish embryos exhibited pericardium enlargement, yolk sac swelling, growth stunting, and abnormal liver development.
- RNA-seq revealed significant alterations in gene expression and metabolic pathways in response to bepridil.
Conclusions:
- Bepridil exhibits significant developmental toxicity, affecting cardiac and liver development in zebrafish embryos.
- The findings suggest potential risks for prenatal cardiac patients using bepridil.
- Further evaluation of antiarrhythmic agents for prenatal use is crucial.
Abstract:
Bepridil is a commonly used medication for arrhythmia and heart failure. It primarily exerts hemodynamic effects by inhibiting Na+/K+ movement and regulating the Na+/Ca2+ exchange. In comparison to other Ca2+ inhibitors, bepridil has a long half-life and a complex pharmacology. Additionally, it is widely used in antiviral research and the treatment of various diseases. However, the toxicity of this compound and its other possible effects on embryonic development are unknown. In this study, we investigated the toxicity of bepridil on rat myocardial H9c2 cells. After treatment with bepridil, the cells became overloaded with Ca2+ and entered a state of cytoplasmic vacuolization and nuclear abnormality. Bepridil treatment resulted in several morphological abnormalities in zebrafish embryo models, including pericardium enlargement, yolk sac swelling, and growth stunting. The hemodynamic effects on fetal development resulted in abnormal cardiovascular circulation and myocardial weakness. After inhibiting the Ca2+ transmembrane, the liver of zebrafish larvae also displayed an ectopic and deficient spatial location. Additionally, the results of the RNA-seq analysis revealed the detailed gene expression profiles and metabolic responses to bepridil treatment in zebrafish embryonic development. Taken together, our study provides an important evaluation of antiarrhythmic agents for clinical use in prenatal heart patients.
