Selective inhibition of persistent sodium current by F 15845 prevents ischaemia-induced arrhythmias

BACKGROUND AND PURPOSE Myocardial ischaemia is associated with perturbations of electrophysiological profile of cardiac myocytes. The persistent sodium current (I-Nap) is one of the major contributors to ischaemic arrhythmias and appears as an attractive therapeutic target. We investigated the effects of F 15845, a new anti-anginal drug on I-Nap and in integrative models of I-Nap-induced arrhythmias. EXPERIMENTAL APPROACH Sodium current was investigated using patch clamp technique on wild-type and Delta KPQ-mutated hNav1.5 channels transfected in HEK293 cells. Effects of F 15845 on action potentials (APs) were studied by the glass microelectrode technique and its anti-arrhythmic activities were investigated in ischaemia- and aconitine-induced arrhythmias in the rat. KEY RESULTS We demonstrated that F 15845 is a potent blocker of I-Nap acting from the extracellular side of the channel. Blockade of I-Nap was voltage dependent and characterized by an almost pure tonic block. F 15845 shortened AP from rabbit Purkinje fibres, confirming its lack of pro-arrhythmic activity, and prevented AP lengthening induced by the I-Nap activator veratridine. F 15845 did not affect APs from rabbit atria and guinea pig papillary muscle where I-Nap is not functional, confirming its inability to affect other cardiac ionic currents. F 15845 was effective at preventing fatal ventricular fibrillation and ventricular tachycardia during coronary ligation without modifying heart rate and blood pressure, and dose dependently increased the dose threshold of aconitine required to induce ventricular arrhythmias. CONCLUSIONS AND IMPLICATIONS F 15845, a novel anti-anginal drug targeting I-Nap, demonstrates new anti-arrhythmic properties which may be of therapeutic benefit against ischaemia-induced arrhythmias.