CONTRIBUTION OF DELAYED RECTIFIER AND INWARD RECTIFIER TO REPOLARIZATION OF THE ACTION-POTENTIAL - PHARMACOLOGICAL SEPARATION

Outward potassium (K) currents contribute to the repolarization process of cardiac action potentials. There are, however, multiple K currents. Recently, two putatively specific K channel blockers have been developed as potential class III antiarrhythmic agents. E-4031 appears to block specifically a fast component of the delayed rectifier (I(K)), and RP 58866 is a reported inward rectifier current (I(K1)) blocker. In the present experiments, we examined the effects of E-4031 and RP 58866 on action potentials recorded from guinea pig papillary muscles to determine whether the properties of I(K) and I(K1) measured in whole-cell experiments would be manifested in distinct effects. Both compounds prolonged the APD50 (action potential duration at 50% repolarization) and AP90 (action potential duration at 90% repolarization). However, RP 58866 did not significantly prolong the action potential at voltages of 0 mV and above, while E-4031 did. The results suggest that preferential I(K1)) block results in a change in action potential waveform that is distinct from that resulting from block of other outward K currents. This could thus be used as a simple first-pass screening tool in determining a preliminary mechanism of action of class III antiarrhythmics prior to more time-consuming but necessary whole-cell voltage clamp experiments.