title: Rabbit models as tools for preclinical cardiac electrophysiological safety testing: Importance of repolarization reserve.
abstract: 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. Also, pre-clinical safety tests utilize several species commonly used in cardiac electrophysiological studies. In this review, important species differences in cardiac ventricular repolarizing ion currents are considered, followed by the discussion on electrical remodeling associated with chronic cardiovascular diseases that leads to altered ion channel and transporter expression and densities in pathological settings. We argue that the choice of species strongly influences experimental outcome and extrapolation of results to human clinical settings. We suggest that based on cardiac cellular electrophysiology, the rabbit is a useful species for pharmacological pro-arrhythmic investigations. In addition to healthy animals and tissues, the use of animal models (e.g. those with impaired repolarization reserve) is suggested that more closely resemble subsets of patients exhibiting increased vulnerability towards the development of ventricular arrhythmias and sudden cardiac death.
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., 6720 Szeged, Hungary. Electronic address: baczko.istvan@med.u-szeged.hu.
authors.forename: István
authors.initials: I
authors.lastname: Baczkó
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., 6720 Szeged, Hungary; MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Dóm tér 12., 6720 Szeged, Hungary.
authors.forename: Norbert
authors.initials: N
authors.lastname: Jost
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., 6720 Szeged, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Virág
authors.affiliation: Rabbit Genome and Biomodel Group, NARIC-Agricultural Biotechnology Institute, 2100 Gödöllő, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Bősze
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., 6720 Szeged, Hungary; MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Dóm tér 12., 6720 Szeged, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Varró
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D004195:Disease Models, Animal; D004594:Electrophysiology / Q000379:methods*; D006321:Heart / Q000502:physiology* / Q000503:physiopathology; D006801:Humans; D008955:Models, Cardiovascular; D011817:Rabbits; D012449:Safety
keywords: Cardiac arrhythmias; I(Ks); Pre-clinical safety testing; Rabbit; Repolarization reserve; Species differences