Abstract
The zebrafish is rapidly emerging as a promising alternative in vivo model for the detection of drug-induced cardiovascular effects. Despite its increasing popularity, the ability of this model to inform the drug development process is often limited by the uncertainties around the quantitative relevance of zebrafish responses compared with nonclinical mammalian species and ultimately humans. In this test of concept study, we provide a comparative quantitative analysis of the in vivo cardiovascular responses of zebrafish, rat, dog, and human to three model compounds (propranolol, losartan, and captopril), which act as modulators of two key systems (beta-adrenergic and renin–angiotensin systems) involved in the regulation of cardiovascular functions. We used in vivo imaging techniques to generate novel experimental data of drug-mediated cardiovascular effects in zebrafish larvae. These data were combined with a database of interspecies mammalian responses (i.e., heart rate, blood flow, vessel diameter, and stroke volume) extracted from the literature to perform a meta-analysis of effect size and direction across multiple species. In spite of the high heterogeneity of study design parameters, our analysis highlighted that zebrafish and human responses were largely comparable in >80% of drug/endpoint combinations. However, it also revealed a high intraspecies variability, which, in some cases, prevented a conclusive interpretation of the drug-induced effect. Despite the shortcomings of our study, the meta-analysis approach, combined with a suitable data visualization strategy, enabled us to observe patterns of response that would likely remain undetected with more traditional methods of qualitative comparative analysis. We propose that expanding this approach to larger datasets encompassing multiple drugs and modes of action would enable a rigorous and systematic assessment of the applicability domain of the zebrafish from both a mechanistic and phenotypic standpoint. This will increase the confidence in its application for the early detection of adverse drug reactions in any major organ system.
Highlights
A considerable number of drug candidates have the potential to alter cardiovascular functions at therapeutically relevant concentrations
A visualization of the six endpoints as integrated cardiovascular functional outputs is displayed in Figure 2, whereas Figure 3 shows the entire set of in vivo data generated during the study
We provide evidence that zebrafish cardiovascular responses to propranolol, losartan, and captopril are largely in agreement with those observed in humans, both in terms of effect size and direction, revealing a striking similarity between the two species
Summary
A considerable number of drug candidates have the potential to alter cardiovascular functions at therapeutically relevant concentrations. To date, the use of in vivo preclinical models is still a key aspect of cardiovascular efficacy and safety assessment (Fliegner et al, 2015; Vargas et al, 2015; Berridge et al, 2016), mainly because of the ability of in vivo testing to capture integrated multiscale processes that cannot be observed outside an intact organism These processes include pharmacokinetic-dependent and metabolism-mediated effects, chronic or delayed toxicity, vascular and hemodynamic alterations, as well as interaction between cardiovascular, nervous, and renal systems (Holzgrefe et al, 2014). As with any animal model, each species mentioned above has both advantages and limitations (e.g., see Holzgrefe et al (2014) and Milani-Nejad and Janssen (2014) for extensive reviews of these aspects); common limitations include high ethical and financial costs, and low throughput potential
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