Identification of a specific radioligand for the cardiac rapidly activating delayed rectifier K+ channel.
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.
Chadwick
C C
CC
Department of Cardiovascular Pharmacology, Sterling Winthrop Pharmaceuticals Research Division, Rensselaer, N.Y. 12144.
Ezrin
A M
AM
O'Connor
B
B
Volberg
W A
WA
Smith
D I
DI
Wedge
K J
KJ
Hill
R J
RJ
Briggs
G M
GM
Pagani
E D
ED
Silver
P J
PJ
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
D000889:Anti-Arrhythmia Agents; D015415:Biomarkers; D008024:Ligands; D010627:Phenethylamines; D015221:Potassium Channels; D013449:Sulfonamides; D014316:Tritium; C063533:dofetilide