title: Assessment of drug-induced proarrhythmia: The importance of study design in the rabbit left ventricular wedge model.
abstract: In the present study, we investigated an impact of the stimulation rate on the detection of the proarrhythmic potential of 10 reference compounds with effects on different cardiac ion channels in the isolated arterially-perfused rabbit left ventricular wedge preparation. The compounds were tested in the wedge model using two distinct protocols; including baseline stimulation at 1-Hz followed by a brief period at 0.5-Hz, either without an additional brief period of 2-Hz stimulation (i.e. Protocol 1) or with 2-Hz stimulation (i.e. Protocol 2). As expected, QT-prolonging drugs (ibutilide and quinidine) prolonged the QT interval, similarly increased the Torsades de Pointes (TdP) score, and elicited early afterdepolarizations (EADs) in both protocols. HMR1556 and JNJ-303 (IKs blockers) also prolonged the QT interval up to 1μM similarly in both protocols. Nifedipine (Ca(2+) antagonist) shortened the QT interval, and reduced force of contraction similarly in both protocols. However, Na(+) channel blockers (Ia, Ib, Ic) widened the QRS duration more in Protocol 2 than in Protocol 1. Furthermore, it was only possible to detect non-TdP-like ventricular tachycardia/fibrillation (VT/VF) induced by Na(+) blockers and by QT-shortening drugs (levcromakalim and mallotoxin) using the 2-Hz stimulation (Protocol 2). Our data suggest that the inclusion of a brief period of fast stimulation at 2Hz is critical for detecting drug-induced slowing of conduction (QRS widening), QT shortening and associated (non-TdP-like) VT/VF, which are distinct from the QT prolongation/TdP proarrhythmia in isolated, arterially-perfused rabbit left ventricular wedges.
authors.affiliation: Global Safety Pharmacology, Discovery Sciences, Janssen Research & Development, Janssen Pharmaceutica NV, Belgium. Electronic address: hlu@its.jnj.com.
authors.forename: Hua Rong
authors.initials: HR
authors.lastname: Lu
authors.affiliation: Global Safety Pharmacology, Discovery Sciences, Janssen Research & Development, Janssen Pharmaceutica NV, Belgium.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gallacher
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA, USA.
authors.forename: Gan-Xin
authors.initials: GX
authors.lastname: Yan
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects* / Q000503:physiopathology*; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D011817:Rabbits; D026941:Sodium Channel Blockers / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000503:physiopathology; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D026941:Sodium Channel Blockers
keywords: Cardiac arrhythmias; Drug; Long QT syndrome; Short QT syndrome; Stimulation rate; TdP: Torsades de Pointes; VF: ventricular fibrillation; VT: ventricular tachycardia