Rabbit a reliable human like model in preclinical cardiac electrophysiological safety testing

[Speaker] Norbert Jost:1,2
[Co-author] Laszlo Virag:1, Istvan Baczko:1, Andras Varro:1,2
1:Department of Pharmacology and Pharmacotherapy, University of Szeged, Hungary, 2:MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungary

Introduction: It is essential to more reliably assess the pro-arrhythmic liability of compounds in development. Current guidelines for pre-clinical and clinical testing of drug candidates advocate the use of healthy animals/tissues and healthy individuals and focus on the test compound's ability to block the hERG current and prolong cardiac ventricular repolarization. In this poster, important species differences in cardiac ventricular repolarizing ion currents are considered. We argue that the choice of species strongly influences experimental outcome and extrapolation of results to human clinical settings. Hereby we suggest that based on cardiac cellular electrophysiology, the rabbit is a useful species for pharmacological pro-arrhythmic investigations.
Methods: Action potentials and ion currents were determined by using standard microelectrode and whole-cell patch clamp technique in ventricular originated from rabbit and undiseased human heart ventricular preparations. Experimental protocols were approved by the University of Szeged and National Scientific and Research Ethical Review Boards-
Results: Rabbit has a very similar action potential (Figure 1) profile when compared with human and dog, Several transmembrane potassium currents were investigated including rapid and slow delayed rectifier (IKr and IKs), inward rectifier (IK1) and transmembrane outward potassium currents (Ito). We found that all investigated potassium currents were similar including amplitude and kinetics (Figures 1B-1D. However, for practical reasons, advantages of rabbit models should be mentioned compared to canine models, these include reduced cost (breeding, animal keeping), the already existing and proven technology for the creation of transgenic animals and favourable ethical considerations (the rabbit is not a pet animal), in spite of the fact that the size of the heart and heart rates of the dog are similar to those in humans.
Conclusions: In conclusion, in cardiac safety testing, although the investigations on healthy animals and individuals are still important, the addition of models recapitulating human disease are definitely needed. These additions are justified in order to test compounds in models that more closely resemble patient subpopulations with increased vulnerability to ventricular arrhythmias and sudden cardiac death, such as congestive heart failure, hypertrophic cardiomyopathy, congenital LQT syndromes and diabetes mellitus.
Suported by GINOP-GINOP-2.3.2-15-2016-00006 grant.

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