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Comparison of binding to rapidly activating delayed rectifier K+ channel, IKr, and effects on myocardial refractoriness for class III antiarrhythmic agents.
- Source :
-
Journal of cardiovascular pharmacology [J Cardiovasc Pharmacol] 1995 Feb; Vol. 25 (2), pp. 336-40. - Publication Year :
- 1995
-
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)
- Subjects :
- Animals
Anti-Arrhythmia Agents metabolism
Binding, Competitive drug effects
Chromans metabolism
Chromans pharmacology
Electrophysiology
Guinea Pigs
Heart Ventricles cytology
Heart Ventricles drug effects
Heart Ventricles metabolism
Papillary Muscles drug effects
Papillary Muscles metabolism
Phenethylamines metabolism
Phenethylamines pharmacology
Piperidines metabolism
Piperidines pharmacology
Potassium Channels metabolism
Procainamide analogs & derivatives
Procainamide metabolism
Procainamide pharmacology
Pyridines metabolism
Pyridines pharmacology
Sotalol metabolism
Sotalol pharmacology
Structure-Activity Relationship
Sulfonamides metabolism
Sulfonamides pharmacology
Tritium metabolism
Anti-Arrhythmia Agents pharmacology
Potassium Channel Blockers
Subjects
Details
- Language :
- English
- ISSN :
- 0160-2446
- Volume :
- 25
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of cardiovascular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 7752661
- Full Text :
- https://doi.org/10.1097/00005344-199502000-00021