Background The class III antiarrhythmic agent RP 58866 and its active enantiomer, terikalant, are reported to selectively block the inward rectifier K⁺ current, I_K1. These drugs have demonstrated efficacy in animal models of cardiac arrhythmias, suggesting that block of I_K1 may be a useful antiarrhythmic mechanism. The symmetrical action potential (AP)–prolonging and bradycardic effects of these drugs, however, are inconsistent with a sole effect on I_K1.

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_Kr, with IC₅₀s of 22 and 31 nmol/L, respectively. Block of I_K1 was ≈250-fold less potent; IC₅₀s were 8 and 6 μmol/L, respectively. No significant block of the slowly activating delayed rectifier, I_Ks, was observed at ≤10 μmol/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 ≤1 μmol/L and dofetilide increased AP duration symmetrically, consistent with selective block of I_Kr. Only higher concentrations (≥10 μmol/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_K1.

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_K1 by these drugs.