Electropharmacology of dofetilide, a new class III agent, in anaesthetised dogs.
In open chest anaesthetised dogs, dofetilide increased the ventricular effective refractory period over the dose range 1-100 micrograms/kg i.v. and the ventricular fibrillation threshold at doses between 3-100 micrograms/kg and was 80-1000 times more potent than sematilide, racemic sotalol, d-sotalol or quinidine. The maximal increases in ventricular fibrillation threshold induced by sematilide and quinidine were less than that induced by the other drugs. A change in the character of the induced arrhythmia from true ventricular fibrillation to a rapid ventricular flutter, with frequent spontaneous conversion, was observed following all drugs. No adverse haemodynamic effects of dofetilide, sematilide or d-sotalol were observed, but quinidine induced marked cardiac depression and racemic sotalol also impaired left ventricular contractility. All drugs reduced heart rate, though the effect of racemic sotalol was clearly greater than that of the other agents. Dofetilide is a potent class III antiarrhythmic agent with antifibrillatory properties and a favourable haemodynamic profile.
Gwilt
M
M
Pfizer Central Research, Sandwich, Kent, U.K.
Blackburn
K J
KJ
Burges
R A
RA
Higgins
A J
AJ
Milne
A A
AA
Solca
A M
AM
D000200:Action Potentials / Q000187:drug effects; D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004285:Dogs; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D010627:Phenethylamines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects; D011342:Procainamide / Q000031:analogs & derivatives / Q000494:pharmacology; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D014693:Ventricular Fibrillation / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D015221:Potassium Channels; D013449:Sulfonamides; C062818:sematilide; D013015:Sotalol; D011342:Procainamide; C063533:dofetilide