Cellular electrophysiology of WAY-123,398, a new class III antiarrhythmic agent: specificity of IK block and lack of reverse use dependence in cat ventricular myocytes

Abstract

Objective: The objectives were (a) to evaluate the effects of WAY-123,398, a new class III antiarrhythmic agent, on the action potential of canine Purkinje fibres in comparison with dofetilide, E-4031, and dl-sotalol, and (b) to characterise the mechanism of the class III action by studying its effects on several ionic currents in isolated cat myocytes.

Methods: Transmembrane potentials in Purkinje fibres were studied with standard microelectrodes filled with 3M KCl. Myocytes were isolated by enzymatic disaggregation with collagenase and current recordings were obtained by voltage clamp with either the nystatin perforated patch technique or the usual whole cell configuration.

Results: WAY-123,398 prolonged action potential duration (APD) in Purkinje fibres and in cat ventricular myocytes without altering other variables of the action potential; in Purkinje fibres the concentration producing a 20% prolongation of APD-60 mV at a basic cycle length of 1000 ms was 0.2 microM. After depolarising voltage steps, the delayed rectifier (IK) peak tail currents in cat myocytes were blocked with IC50 = 0.1 microM. The block was unaffected by varying the duration (200 to 500 ms) or the frequency (0.4 to 2.5 Hz) of the depolarising steps. A much higher concentration of WAY-123,398 (10 microM) did not have effects on the L type Ca current (ICa-L), and on the inward rectifier (IK1) and transient outward (I(to)) K currents.

Conclusions: The results indicate that WAY-123,398 is an effective and specific class III agent devoid of class I activity, and suggest that WAY-123,398 prolongs cardiac repolarisation by specifically blocking the delayed rectifier current (IK). The block was unchanged over a range of frequencies and duration of depolarisation, showing no evidence of "reverse use dependence" of block.