Drug-induced long QT in isolated rabbit Purkinje fibers: importance of action potential duration, triangulation and early afterdepolarizations

Abstract

In the present study, we investigated three drug-induced long-QT syndromes in isolated rabbit Purkinje fibers in order to identify the relationship of action potential duration (APD), triangulation of action potentials (APD 90–APD 40) and early afterdepolarizations. Isolated rabbit Purkinje fibers were superperfused in Tyrode solution with solvent, indapamide (1×10 −4 M, an I ks blocker mimicking long QT1), dofetilide (1×10 −9, 1×10 −8 or 1×10 −7 M, an I kr blocker mimicking long QT2) or anthopleurin (1×10 −8 M, an inhibitor of the inactivation of the I Na + current mimicking long QT3) ( n=8 per group) for 25 min, and stimulated at 1 Hz for 20 min and at 0.2 Hz for another 5 min. Indapamide did not change APD and triangulation or elicit early afterdepolarizations even in the presence of β-adrenergic stimulation with isoproterenol. Dofetilide concentration-dependently prolonged APD 90, increased triangulation and elicited early afterdepolarizations. Anthopleurin markedly increased APD 90 as well as triangulation and elicited early afterdepolarizations. The induction of early afterdepolarizations by dofetilide and anthopleurin was associated with a prolongation of APD 90 or an increase in triangulation, but not with a change in APD 40. Moreover, the degree of the increase in the triangulation was larger than that of APD 90 in long QT2 (dofetilide-induced) and long QT3 (anthopleurin-induced) models in isolated rabbit Purkinje fibers. Our present study indicates that rabbit Purkinje fibers can be used as long QT2 (dofetilide-mimicking) and LQT3 (anthopleurin-mimicking) syndrome models, and confirms that drug-induced long QT1 (indapamide-mimicking) is absent. Our present study also shows the relationship between a prolongation of APD 90 or increase in triangulation and the induction of early afterdepolarizations with dofetilide ( I kr blocker) and anthopleurin ( I Na modulator) in isolated rabbit Purkinje fibers.