Differentiating multichannel block on the guinea pig ECG: Use of T_peak-T_end and J-T_peak

The anaesthetised guinea pig is a well characterised assay for early assessment of drug effects on ventricular repolarisation and risk of Torsade de Pointes (TdP). We assessed whether a selective hERG blocker with known TdP risk could be differentiated from lower risk, balanced ion channel blockers in the guinea pig, using corrected QT (QTc) interval alongside novel electrocardiogram (ECG) biomarkers J-T_peakc and T_peak-T_end. Effects were compared with previous clinical investigations at similar plasma concentrations and with another index of TdP risk, the electromechanical window (EMW).

Twenty-two Dunkin Hartley guinea pigs anaesthetised with sodium pentobarbitone were instrumented for haemodynamic measurement and ECG recording. Three ascending doses of vehicle (n = 6), dofetilide (2, 6 or 20 μg/kg; n = 7), ranolazine (2, 6 or 20 mg/kg; n = 5) or verapamil (0.1, 0.3 or 1.0 mg/kg; n = 4) were administered intravenously.

As reported in previous clinical studies, dofetilide induced dose-dependent increases in QTc interval, with increases in both J-T_peakC or T_peak-T_end, while verapamil caused no significant increase in QTc interval, J-T_peakC or T_peak-T_end. Ranolazine caused dose-dependent increases in QTc interval and corrected J-T_peakc, but had no effect on T_peak-T_end, which is in contrast to the effects reported in humans at similar concentrations. Only dofetilide caused a clear, dose-related decrease in the EMW.

These findings suggest that measurements of J-T_peakc and T_peak-T_end in addition to QT interval, may help differentiate pure hERG channel blockers with high risk of TdP from lower risk, multichannel blockers.