The comparative sensitivity of three in vitro safety pharmacology models for the detection of lidocaine-induced cardiac effects.

INTRODUCTION: In the current ICH S7B guideline, in vitro evaluation of proarrhythmic liability is limited to the risk of QT interval prolongation, whilst the effect of new chemical entities on cardiac conductivity is often overlooked. The aim of this work was to compare the effects of the sodium channel blocker, lidocaine in three in vitro safety pharmacology models: hNa(v)1.5 channel test, atrial action potential (AP) and Purkinje fiber AP and to identify the most sensitive model for detecting cardiac conduction slowing.
METHODS: Whole-cell patch-clamp methods were used to record the sodium current (I(Na)) encoded by hNa(v)1.5 in stably transfected HEK293 cells at ambient temperature. Transmembrane APs were recorded in rabbit Purkinje fibers and rabbit and guinea-pig left stimulated atria at physiological temperature. Parameters involved in depolarization or repolarization were reported.
RESULTS: Lidocaine (from 10 to 1000 μM) decreased the amplitude of I(Na) (IC(50): 256±37 μM) in a concentration-dependent manner. In the Purkinje fiber assay, lidocaine (10, 30 and 100 μM) had no effects on maximal upstroke velocity (Vmax), but shortened AP duration at 90% repolarization (APD(90)). At 30 and 100 μM, lidocaine also increased AP triangulation. In guinea-pig atria, lidocaine decreased Vmax starting from 30 μM and conduction velocity (CV) at 100 μM, but had no effects on other parameters. In rabbit atria, lidocaine decreased Vmax and CV at 100 μM without affecting APD(90). The effects of 100 μM lidocaine on Vmax and CV were more marked in rabbit than in guinea-pig atria.
CONCLUSION: Rabbit atria are more sensitive than rabbit Purkinje fibers or guinea-pig atria for detecting lidocaine-induced cardiac conduction slowing. These data suggest that isolated rabbit atria in addition to the hNa(v)1.5 channel assay could be relevant models to predict drug-induced conduction slowing.