title: Identification of a specific radioligand for the cardiac rapidly activating delayed rectifier K+ channel.
abstract: Class III antiarrhythmic drugs show promise as effective treatments for the suppression of potentially lethal cardiac arrhythmias. Dofetilide (UK-68,798), is a potent class III antiarrhythmic agent that is presently under clinical investigation. The objective of this study was to determine whether [3H]dofetilide could be used as a specific radioligand for the rapidly activating delayed rectifier K+ channel of the heart. We find that [3H]dofetilide binds to high-affinity sites on guinea pig cardiac myocytes. Competition studies using unlabeled dofetilide indicate that binding is characterized by an IC50 of 100 +/- 30 nM (mean +/- SD, n = 13). Scatchard analyses of binding indicate a Kd of 70 +/- 6 nM and a maximal binding capacity of 0.30 +/- 0.02 pmol/mg protein. [3H]Dofetilide is displaced from guinea pig myocytes by dofetilide, clofilium, quinidine, sotalol, and sematilide with a rank order of potency that correlates with functional blockade of the rapidly activating delayed rectifier K+ current (correlation coefficient, 0.951; slope, 0.99 +/- 0.19; p = 0.014). High-affinity [3H]dofetilide binding is not detected in rat myocytes, which are devoid of delayed rectifier K+ current. We conclude that [3H]dofetilide specifically binds to sites associated with the rapidly activating delayed rectifier K+ channel of guinea pig myocardium.
authors.affiliation: Department of Cardiovascular Pharmacology, Sterling Winthrop Pharmaceuticals Research Division, Rensselaer, N.Y. 12144.
authors.forename: C C
authors.initials: CC
authors.lastname: Chadwick
authors.forename: A M
authors.initials: AM
authors.lastname: Ezrin
authors.forename: B
authors.initials: B
authors.lastname: O'Connor
authors.forename: W A
authors.initials: WA
authors.lastname: Volberg
authors.forename: D I
authors.initials: DI
authors.lastname: Smith
authors.forename: K J
authors.initials: KJ
authors.lastname: Wedge
authors.forename: R J
authors.initials: RJ
authors.lastname: Hill
authors.forename: G M
authors.initials: GM
authors.lastname: Briggs
authors.forename: E D
authors.initials: ED
authors.lastname: Pagani
authors.forename: P J
authors.initials: PJ
authors.lastname: Silver
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D015415:Biomarkers; D006168:Guinea Pigs; D008024:Ligands; D008297:Male; D010627:Phenethylamines / Q000737:chemistry* / Q000378:metabolism; D015221:Potassium Channels / Q000737:chemistry*; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism; D014316:Tritium
chemical_list: D000889:Anti-Arrhythmia Agents; D015415:Biomarkers; D008024:Ligands; D010627:Phenethylamines; D015221:Potassium Channels; D013449:Sulfonamides; D014316:Tritium; C063533:dofetilide