Membrane activity of class III antiarrhythmic compounds; a comparison between ibutilide, d-sotalol, E-4031, sematilide and dofetilide.
This study compares the membrane activity of ibutilide, d-sotalol, sematilide, E-4031 and dofetilide on single ventricular cells under identical experimental conditions. We found that ibutilide and dofetilide produced a 'bell-shaped' concentration-dependent effect on action potential duration. Ionic current measurement showed that ibutilide, at 10(-8) M, increased a late inward current; the other compounds had either no effect or decreased it. Moreover, only ibutilide, at a high concentration of 10(-5) M, increased an outward current, as oppose to a uniform depression of IK by d-sotalol, sematilide, E-4031 and dofetilide, and the depression of IK by the latter compounds could be reversed by 10(-5) M ibutilide. Finally, low concentration of ibutilide could further prolong the action potential duration that had already been prolonged by a K+ channel blocker, but a high concentration of ibutilide did just the opposite by reversing the prolongation caused by K+ channel blockers. Therefore, action potentials agree well with the ionic current results. Possible mechanistic advantage of ibutilide over K+ channel blockers was discussed.
Lee
K S
KS
Cardiovascular Diseases Research, Upjohn Co., Kalamazoo, MI 49007.
Tsai
T D
TD
Lee
E W
EW
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D010627:Phenethylamines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D011342:Procainamide / Q000031:analogs & derivatives / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D010880:Piperidines; D015221:Potassium Channels; D011725:Pyridines; D013449:Sulfonamides; C062818:sematilide; C063968:E 4031; C067192:ibutilide; D013015:Sotalol; D011342:Procainamide; C063533:dofetilide