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(Circulation. 1996;94:2938-2946.)
© 1996 American Heart Association, Inc.

Articles

Mechanism of Action Potential Prolongation by RP 58866 and Its Active Enantiomer, Terikalant

Block of the Rapidly Activating Delayed Rectifier K⁺ Current, I_Kr

Nancy K. Jurkiewicz, BS; Jixin Wang, MS; Bernard Fermini, PhD; Michael C. Sanguinetti, PhD; Joseph J. Salata, PhD

the Department of Pharmacology, Merck Research Laboratories, West Point, Pa, and the Cardiology Division and Eccles Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City (M.C.S.).

Correspondence to Joseph J. Salata, Department of Pharmacology, Merck Research Laboratories, Sumneytown Pike, PO Box 4, WP46-300, West Point, PA 19486. E-mail joseph_salata@merck.com.

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.

Key Words: action potentials • antiarrhythmia agents • electrophysiology • potassium • dofetilide

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