Comparison of bidisomide, flecainide and dofetilide on action potential duration in isolated canine atria: effect of isoproterenol.
Prolongation of action potential duration (APD) and the effective refractory period (ERP) is one mechanism to prevent reentrant atrial and ventricular arrhythmias. Because arrhythmias are usually associated with an elevated sympathetic tone and increase of circulating catecholamines, the potential influence of catecholamines on antiarrhythmic effects of an agent are critical to predicting the potential clinical response. In this study the effects of three different antiarrhythmic agents, bidisomide, flecainide and dofetillide, each of which prolongs atrial ERP, were compared before and after treatment with isoproterenol, a beta-adrenergic agonist. Standard intracellular microelectrode recording techniques were used to record action potentials from isolated canine atrial tissue. Bidisomide and flecainide elicited a 20 to 27 msec increase in APD and ERP that was independent of stimulation frequency (1-5 Hz). Dofetilide prolonged APD and ERP at 1 Hz (40 and 37 msec, respectively) but was completely ineffective at 5 Hz. After equilibration with the anti-arrhythmic agent, tissues were additionally exposed to isoproterenol. Only bidisomide prolonged APD and ERP in the presence of isoproterenol. In the converse series of experiments after treatment with isoproterenol, which caused a 20 to 30% reduction in APD and ERP, only bidisomide completely reversed the effect of 1 microM isoproterenol. Bidisomide was inactive in a functional beta-adrenergic antagonism assay, thus ruling out beta-adrenergic blockade as a potential mechanism. These results indicate that bidisomide, unlike flecainide and dofetilide was able to prolong APD and ERP in isolated canine atrium even at high stimulation frequencies and in the presence of isoproterenol. These data suggest that bidisomide would be effective in the presence of elevated sympathetic tone and on the agents studied, only bidisomide possessed a unique and desirable antiarrhythmic profile.
Martin
C L
CL
SEARLE, Research and Development, Skokie, IL 60077, USA.
Palomo
M A
MA
Mcmahon
E G
EG
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005424:Flecainide / Q000494:pharmacology*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D010880:Piperidines; D013449:Sulfonamides; C061991:bidisomide; D005424:Flecainide; D007545:Isoproterenol; C063533:dofetilide