CELLULAR ELECTROPHYSIOLOGY OF WAY-123,398, A NEW CLASS-III ANTIARRHYTHMIC AGENT - SPECIFICITY OF I(K) BLOCK AND LACK OF REVERSE USE DEPENDENCE IN CAT VENTRICULAR MYOCYTES

Objective: The objectives were (a) to evaluate the effects of WAY- 1 2 3,398, a new class III antiarrhythmic agent, on the action potential o f canine Purkinje fibres in comparison with dofetilide, E-4031, and dl -sotalol, and (b) to characterise the mechanism of the class III actio n by studying its effects on several ionic currents in isolated cat my ocytes. Methods: Transmembrane potentials in Purkinje fibres were stud ied with standard microelectrodes filled with 3M KCl. Myocytes were is olated by enzymatic disaggregation with collagenase and current record ings were obtained by voltage clamp with either the nystatin perforate d patch technique or the usual whole cell configuration. Results: WAY- 123,398 prolonged action potential duration (APD) in Purkinje fibres a nd 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 muM. After depolarising voltage steps, the delayed rectifier (I(K)) p eak tail currents in cat myocytes were blocked with IC50=0.1 muM. The block was unaffected by varying the duration (200 to 500 ms) or the fr equency (0.4 to 2.5 Hz) of the depolarising steps. A much higher conce ntration of WAY-123,398 (10 muM) did not have effects on the L type Ca current (I(Ca-L)), and on the inward rectifier (I(Kl)) and transient outward (1(to)) K currents. Conclusions: The results indicate that WAY -123,398 is an effective and specific class Ill agent devoid of class I activity, and suggest that WAY-123,398 prolongs cardiac repolarisati on by specifically blocking the delayed rectifier current (I(K)). The block was unchanged over a range of frequencies and duration of depola risation, showing no evidence of ''reverse use dependence'' of block.