title: Comparison of binding to rapidly activating delayed rectifier K+ channel, IKr, and effects on myocardial refractoriness for class III antiarrhythmic agents.
abstract: Saturation binding studies in guinea pig ventricular myocytes with 3H-dofetilide, a radioligand for the cardiac rapidly activating delayed rectifier K+ IKr channel, indicated specific high-affinity binding with a Kd of 83 nM and a Bmax of 0.18 pmol/mg cellular protein (1.36 x 10(6) sites/cell). Using displacement of high-affinity 3H-dofetilide binding as a measure of interaction with the IKr channel, potencies (Ki values) for binding to the IKr channel in guinea pig myocytes for six class III antiarrhythmic agents were characterized and compared to indices of functional electrophysiologic activity in isolated guinea pig papillary muscles [EC25 values, concentration required to increase effective refractory period (ERP) 25% above baseline]. Dofetilide, E-4031, sematilide, and d-sotalol, which have been characterized previously as selective IKr blockers, displayed good agreement between Ki values for displacement of 3H-dofetilide binding (47 +/- 7 nM, 38 +/- 8 nM, 12 +/- 5 microM, and approximately 100 microM, respectively) and EC25 values for increasing ERP in papillary muscles (45.0 nM, 76.9 nM, 20.2 microM and 63.5 microM, respectively). Ibutilide and RP58866, which have been reported to act via mechanisms other than IKr block, had Ki values for displacement of 3H-dofetilide binding (16 +/- 7 nM and 17 +/- 2 nM, respectively) that were approximately 10-fold lower than EC25 values for increasing ERP in papillary muscles (185.8 nM and 223.5 nM, respectively). The potent displacement of high-affinity 3H-dofetilide binding by ibutilide and RP58866 strongly suggest a role for interaction with IKr in their actions.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, PA 19446, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: E P
authors.initials: EP
authors.lastname: Baskin
authors.forename: E M
authors.initials: EM
authors.lastname: Nutt
authors.forename: P J
authors.initials: PJ
authors.lastname: Guinosso
authors.forename: T
authors.initials: T
authors.lastname: Hamill
authors.forename: J J
authors.initials: JJ
authors.lastname: Salata
authors.forename: C M
authors.initials: CM
authors.lastname: Woods
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002839:Chromans / Q000378:metabolism / Q000494:pharmacology; D004594:Electrophysiology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism; D010627:Phenethylamines / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D011342:Procainamide / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D013015:Sotalol / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D002839:Chromans; D010627:Phenethylamines; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011725:Pyridines; D013449:Sulfonamides; C062818:sematilide; D014316:Tritium; C063968:E 4031; C067192:ibutilide; D013015:Sotalol; C063899:terikalant; D011342:Procainamide; C063533:dofetilide