Effects of WAY-123,398, a new class III antiarrhythmic agent, on cardiac refractoriness and ventricular fibrillation threshold in anesthetized dogs: a comparison with UK-68798, E-4031, and dl-sotalol.
Previous studies in isolated ventricular myocytes showed that WAY-123,398 is a selective blocker of the delayed rectifier K+ current (IK). In this report, we studied the electrophysiological and hemodynamic effects of WAY-123,398 in open-chest anesthetized dogs. WAY-123,398 prolonged atrial and ventricular refractoriness without affecting conduction; WAY-123,398 was as effective as UK-68798, E-4031, and dl-sotalol, but less potent than UK-68798 and E-4031. The increase in atrial refractoriness was approximately twice as large as the ventricular increase with all compounds. The hemodynamic effects of WAY-123,398 were similar to those of UK-68798; at the ED20 for increasing ventricular refractoriness, WAY-123,398 did not affect the mean arterial pressure and decreased the heart rate by 20%. In a different series of experiments, all four compounds produced large and comparable increases in the ventricular fibrillation threshold in anesthetized dogs; WAY-123,398 and UK-68798 induced defibrillation and restoration of sinus rhythm in two of six dogs each and E-4031 in one of six dogs. No episodes of drug-induced restoration to sinus rhythm were observed in dogs treated with sotalol or vehicle. In conclusion, WAY-123,398 is an effective Class III agent without Class I actions and with a favorable hemodynamic profile.
D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001283:Atrioventricular Node / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D004285:Dogs; D004562:Electrocardiography; D004594:Electrophysiology; D005260:Female; D006321:Heart / Q000187:drug effects*; D006329:Heart Conduction System / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D012032:Refractory Period, Electrophysiological / Q000187:drug effects*; D013015:Sotalol / Q000494:pharmacology; D013424:Sulfanilamides / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D014693:Ventricular Fibrillation / Q000503:physiopathology*; D000096926:Benzenesulfonamides
D000889:Anti-Arrhythmia Agents; D001562:Benzimidazoles; D010627:Phenethylamines; D010880:Piperidines; D011725:Pyridines; D013015:Sotalol; D013424:Sulfanilamides; D013449:Sulfonamides; C063968:E 4031; C073190:WAY 123398; D000096926:Benzenesulfonamides; C063533:dofetilide