Choice of cardiac tissue in vitro plays an important role in assessing the risk of drug-induced cardiac arrhythmias in human: Beyond QT prolongation

Abstract

Introduction Recently we have demonstrated that to the choice of tissue type is important in identifying I Kr and I Ks-induced prolongation of the action potential. However, the differential sensitivity of cardiac tissues to other ionic current blockers or modulators is relatively unknown. The aim of the present study was therefore to evaluate tissue-specific effects of different ion channel blockers or activators on the action potential (AP), which can affect other parameters in addition to drug-induced APD/QT prolongation or shortening. Methods and Results Electrophysiological effects were measured in isolated rabbit Purkinje fibers, papillary muscles and ventricular trabeculae using a microelectrode technique under the following conditions: block of I to with 4-AP (1 × 10 − 3 M), block of Ca 2+ channels with diltiazem (1 × 10 − 5 M), block of Na + channels with flecainide (1 × 10 − 5 M), activation of Ca 2+ current with Bay-K-8644 (1 × 10 − 5 M), activation of K ATP channels with levcromakalim (1 × 10 − 5 M) or block of I K1 current with BaCl 2 ( n = 8 to 12 for each group). 4-AP prolonged APD significantly more in the Purkinje fiber than in the papillary muscle or the ventricular trabecula. 4-AP elicited 63% incidence of early afterdepolarizations but 0% in the papillary or trabeculae. Diltiazem and flecainide shortened APD 40 and APD 50 and increased triangulation more in the Purkinje fiber, whilst having little effect on these parameters in the papillary muscle or the ventricular trabecula. Bay-K-8644 significantly prolonged APD in the ventricular trabecula, but not in the Purkinje fiber or the papillary muscle. BaCl 2 prolonged APD 90 in all tissues, but significantly shortened APD 40 only in the Purkinje fiber. Levcromakalim shortened APD in all tissues, but significantly less in the Purkinje fibers. Conclusion The present study demonstrates that certain cardiac tissues respond differently to the same ion channel blockers/activators, which are not involved in APD/QT prolongation. As such the appropriate selection of tissue needs to be taken into careful consideration in cardiac safety assessments when exploring different mechanisms of drug-induced changes in the action potential.