Corrias A, Giles W, Rodriguez B. Ionic mechanisms of electrophysiological properties and repolarization abnormalities in rabbit Purkinje fibers. Am J Physiol Heart Circ Physiol 300: H1806-H1813, 2011. First published February 18, 2011 doi:10.1152/ajpheart.01170.2010.-Purkinje cells play an important role in drug-induced arrhythmogenesis and are widely used in preclinical drug safety assessments. Repolarization abnormalities such as action potential (AP) prolongation and early afterdeploarizations (EAD) are often observed in vitro upon pharmacological interventions. However, because drugs do not act on only one defined target, it is often difficult to fully explain the mechanisms of action and their potential arrhythmogenicity. Computational models, when appropriately detailed and validated, can be used to gain mechanistic insights into the mechanisms of action of certain drugs. Nevertheless, no model of Purkinje electrophysiology that is able to reproduce characteristic Purkinje responses to drug-induced changes in ionic current conductances such as AP prolongation and EAD generation currently exists. In this study, a novel biophysically detailed model of rabbit Purkinje electrophysiology was developed by integration of data from voltage-clamp and AP experimental recordings. Upon validation, we demonstrate that the model reproduces many key electrophysiological properties of rabbit Purkinje cells. These include: AP morphology and duration, both input resistance and rate dependence properties as well as response to hyperkalemia. Pharmacological interventions such as inward rectifier K ϩ current and rapid delayed rectifier K ϩ current block as well as late Na ϩ current increase result in significant AP changes. However, enhanced L-type Ca 2ϩ current (iCaL) dominates in EAD genesis in Purkinje fibers. In addition, iCaL inactivation dynamics and intercellular coupling in tissue strongly modulate EAD formation. We conclude that EAD generation in Purkinje cells is mediated by an increase in iCaL and modulated by its inactivation kinetics. electrophysiology; Purkinje; early afterdepolarization; arrhythmia FOR DECADES, PURKINJE FIBERS have been implicated in the initiation of lethal cardiac arrhythmias such as ventricular fibrillation and Torsades de Pointes in a variety of clinical situations. In patients with congenital long QT syndrome or Brugada syndrome, for example, the Purkinje-myocardial interface is often the location where ventricular fibrillation initiated (15). Adverse side effects of drugs belonging to a broad range of categories are important factors that have long been associated with arrhythmogenesis. Regulatory agencies have identified Purkinje fibers as an important tool in preclinical assessment of drug safety. Both the Food and Drug Administration and the European Medicines Agency recommend the Purkinje fiber assay for in vitro electrophysiological studies as valuable for assessing potential arrhythmogenicity of a tested compound (41). Aubert et al. (2) have specifically evaluated the rabbit Purkinj...
