Mechanism of action potential prolongation by RP 58866 and its active enantiomer, terikalant - Block of the rapidly activating delayed rectifier K+ current, I-Kr

Background The class III antiarrhythmic agent RP 58866 and its active enantiomer, terikalant, are reported to selectively block the inward rectifier K+ current, I-Kl. These drugs have demonstrated efficacy in animal models of cardia arrhythmias, suggesting that block of I-Kl may be a useful antiarrhythmic mechanism. The symmetrical action potential (AP)-prolonging and bradycardiac effects of these drugs, however, are inconsistent with a sole effect on I-Kl. Methods and Results We studied the effects of RP 58866 and terikalant on AP and outward K+ currents in guinea pig ventricular myocytes. RP 58866 and terikalant potently blocked the rapidly activating delayed rectifier K+ current, I-Ke, with IC50s of 22 and 31 nmol/L, respectively. Block of K-Il was approximate to 250-fold less potent; IC50s were 8 and 6 mu mol/L, respectively. No significant block of the slowly activating delayed rectifier, I-Ks, was observed at less than or equal to 10 mu mol/L. The phenotypical I-Kr currents in mouse AT-1 cells and Xenopus oocytes expressing HERG were also blocked 50% by 200 to 250 nmol/L RP 58866 or terikalant, providing further conclusive evidence for potent block of I-Kr. RP 58866 less than or equal to 1 mu mol/L and dofetilide increased AP duration symmetrically, consistent with selective block of I-Kr. Only higher concentrations (greater than or equal to 10 mu mol/L) of RP 58866 slowed the rate of AP repolarization and decreased resting membrane potential, consistent with an additional but substantially less potent block of I-Kl. Conclusions These data demonstrate that RP 58866 and terikalant are potent blockers of I-Kr and prompt a reinterpretation of previous studies that assumed specific block of I-Kl by these drugs.