title: Mechanism of action potential prolongation by RP 58866 and its active enantiomer, terikalant. Block of the rapidly activating delayed rectifier K+ current, IKr.
abstract: BACKGROUND
  The class III antiarrhythmic agent RP 58866 and its active enantiomer, terikalant, are reported to selectively block the inward rectifier K+ current, IK1. These drugs have demonstrated efficacy in animal models of cardiac arrhythmias, suggesting that block of IK1 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 IK1.
  
  
  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, IKr, with IC50S of 22 and 31 nmol/L, respectively. Block of IK1 was approximately 250-fold less potent; IC50S were 8 and 6 mumol/L, respectively. No significant block of the slowly activating delayed rectifier, IK1, was observed at < or = 10 mumol/L. The phenotypical IKr 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 IKr. RP 58866 < or = 1 mumol/L and dofetilide increased AP duration symmetrically, consistent with selective block of IKr. Only higher concentrations (> or = 10 mumol/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 IK1.
  
  
  CONCLUSIONS
  These data demonstrate that RP 58866 and terikalant are potent blockers of IKr and prompt a reinterpretation of previous studies that assumed specific block of IK1 by these drugs.
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, Pa, USA.
authors.forename: N K
authors.initials: NK
authors.lastname: Jurkiewicz
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: B
authors.initials: B
authors.lastname: Fermini
authors.forename: M C
authors.initials: MC
authors.lastname: Sanguinetti
authors.forename: J J
authors.initials: JJ
authors.lastname: Salata
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D027682:Cation Transport Proteins; D002839:Chromans / Q000494:pharmacology*; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004553:Electric Conductivity; D051638:Ether-A-Go-Go Potassium Channels; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D009206:Myocardium / Q000166:cytology; D009865:Oocytes / Q000378:metabolism; D009994:Osmolar Concentration; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D011188:Potassium / Q000037:antagonists & inhibitors* / Q000502:physiology; D015221:Potassium Channels / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011930:Reaction Time / Q000187:drug effects; D013237:Stereoisomerism; D015534:Trans-Activators; D014981:Xenopus
chemical_list: D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D002839:Chromans; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D010880:Piperidines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; C063899:terikalant; D011188:Potassium