A multi-endpoint in vivo larval zebrafish (Danio rerio) model for the assessment of integrated cardiovascular function

维拉帕米 药理学 斑马鱼 体内 特非那定 医学 纳多洛尔 达尼奥 变时性 内科学 心脏病学 心率 生物 普萘洛尔 血压 生物技术 基因 生物化学
作者
Thomas S. Parker,Paul‐Antoine Libourel,Malcolm J. Hetheridge,Robert I. Cumming,Thomas P. Sutcliffe,Alexander C. Goonesinghe,Jonathan S. Ball,Stewart F. Owen,Yann Chomis,Matthew J. Winter
出处
期刊:Journal of Pharmacological and Toxicological Methods [Elsevier]
卷期号:69 (1): 30-38 被引量:61
标识
DOI:10.1016/j.vascn.2013.10.002
摘要

Despite effective in vitro preclinical strategies to identify cardiovascular (CV) liabilities, there remains a need for early functional assessment prior to complex in vivo mammalian models. The larval zebrafish (Danio rerio, Zf) has been suggested for this role: previous data suggest that cardiac electrophysiology and vascular ultrastructure are comparable with mammals, and also indicate responsiveness of individual Zf CV system endpoints to some functional modulators. Little information is, however, available regarding integrated functional CV responses to drug treatment. Consequently, we developed a novel larval Zf model capable of simultaneous quantification of chronotropic, inotropic and arrhythmic effects, alongside measures of blood flow and vessel diameter.Non-invasive video analysis of the heart and dorsal aorta of anaesthetized and agarose-embedded larval ZF was used to measure multiple cardiovascular endpoints, simultaneously, following treatment with a range of functional modulators of CV physiology.Changes in atrial and ventricular beat frequencies were detected in response to acute treatment with cardio-stimulants (adrenaline and theophylline), and negative chrono/inotropes (cisapride, haloperidol, terfenadine and verapamil). Arrhythmias were also observed including terfenadine-induced 2:1 atrial-ventricular (A-V) block, a previously proposed hERG surrogate measure. Significant increases in blood flow were detected in response to adrenaline and theophylline exposure; and decreases after cisapride, haloperidol, terfenadine, and verapamil treatment. Using dorsal aorta (DA) blood flow and ventricular beat rate, surrogate stoke volumes were also calculated for all compounds.These data support the use of this approach for CV function studies. Moreover the throughput and compound requirements (approximately 3 compounds/person effort/week and <10 mg) make our approach potentially suitable for higher throughput drug safety and efficacy applications, pending further assessment of ZF-mammalian pharmacological comparability.
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