Negative electro-mechanical windows are required for drug-induced Torsades de Pointes in the anesthetized guinea pig

Guns, P.-J.; Johnson, D.M.; Weltens, E. and Lissens, J. (2012). Negative electro-mechanical windows are required for drug-induced Torsades de Pointes in the anesthetized guinea pig. Journal of Pharmacological and Toxicological Methods, 66(2) pp. 125–134.

DOI: https://doi.org/10.1016/j.vascn.2012.03.007

Abstract

Introduction

Assessment of the propensity of novel drugs to cause proarrhythmia is essential in the drug development process. It is increasingly recognized, however, that QT prolongation alone is an imperfect surrogate marker for Torsades de Pointes (TdP) arrhythmia prediction. In the present study we investigated the behavior of a novel surrogate marker for TdP, the electro-mechanical (E-M) window, prior to triggering of TdP episodes with sympathetic stimulation after administration of a number of reference compounds.

Methods

Experiments were carried out in closed chest pentobarbital anesthetized guinea pigs. Test compounds were administered intravenously together with a specific I_Ks blocker (JNJ303; 0.2 mg kg⁻¹ min⁻² for 3 min) and adrenaline (0.06 mg kg− 1 min− 1 for 2 min) was applied to trigger TdP. ECG, blood- and left ventricular pressure signals were measured continuously throughout the experiments. The E-M window i.e. the duration of the mechanical systole (QLVPend interval) minus the duration of the electrical activity (QT interval) was assessed for individual beats.

Results

Drugs with documented TdP liability (quinidine, haloperidol, domperidone, terfenadine, moxifloxacin, ciprofloxacin and dofetilide) produced TdP in the protocol after adrenaline infusion, whereas negative control compounds (verapamil, ranolazine, amiodarone and saline) did not cause TdP arrhythmia, even though increases in repolarization times were observed. TdP were typically preceded by large (greater than − 50 ms) negative electro-mechanical windows and were accompanied by aftercontractions.

Discussion

The present study in anesthetized guinea pigs indicates that negative E-M windows are a prerequisite for sympathetically-driven TdP induction after the administration of various agents with known proarrhythmic potential. These data are a first step in the validation of this novel protocol; however we believe that this proarrhythmia model in small animals might be a valuable additional tool in the prediction of TdP risk of new chemical entities at the early stages of drug discovery.

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