Combined inhibition of key potassium currents has different effects on cardiac repolarization reserve and arrhythmia susceptibility in dogs and rabbits

A reliable assessment of the pro-arrhythmic potential for drugs in the development phase remains elusive. Rabbits and dogs are commonly used to create models of pro-arrhythmia, but the differences between them with respect to repolarizing potassium currents are poorly understood. We investigated the incidence of drug-induced torsades de pointes (TdP) and measured conventional ECG parameters and the short-term variability of the QT interval (STV_QT) following combined pharmacological inhibition of I _K1+I _Ks and I _K1+I _Kr in conscious dogs and anesthetized rabbits. A high incidence of TdP was observed following the combined inhibition of I _K1+I _Ks in dogs (67% vs. 14% in rabbits). Rabbits exhibited higher TdP incidence after inhibition of I _K1+I _Kr (72% vs. 14% in dogs). Increased TdP incidence was associated with significantly larger STV_QT in both models. The relatively different roles of I _K1 and I _Ks in dog and rabbit repolarization reserve should be taken into account when extrapolating the results from animal models of pro-arrhythmia to humans. A stronger repolarization reserve in dogs (likely due to stronger I _K1 and I _Ks), and the more human-like susceptibility to arrhythmia of rabbits argues for the preferred use of rabbits in the evaluation of adverse pro-arrhythmic effects.