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 refr actory period (ERP) is one mechanism to prevent reentrant atrial and v entricular arrhythmias. Because arrhythmias are usually associated wit h an elevated sympathetic tone and increase of circulating catecholami nes, tile potential influence of catecholamines on antiarrhythmic effe cts of an agent are critical to predicting the potential clinical resp onse. In this study the effects of three different antiarrhythmic agen ts, bidisomide, flecainide and dofetilide, each of which prolongs atri al ERP, were compared before and after treatment with isoproterenol, a beta-adrenergic agonist. Standard intracellular microelectrode record ing techniques were used to record action potentials from isolated can ine 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 HIV (40 and 37 msec, r espectively) but was completely ineffective at 5 Hz. After equilibrati on with the antiarrhythmic 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 treatme nt with isoproterenol, which caused a 20 to 30% reduction in APD and E RP, only bidisomide completely reversed the effect of 1 mu M isoproter enol. Bidisomide was inactive in a functional beta-adrenergic antagoni sm assay, thus ruling out beta-adrenergic blockade as a potential mech anism. These results indicate that bidisomide, unlike flecainide and d ofetilide, was able to prolong APD and ERP in isolated canine atrium e ven at high stimulation frequencies and in the presence of isoproteren ol. These data suggest that bidisomide would be effective in the prese nce of elevated sympathetic tone and of the agents studied, only bidis omide possessed a unique and desirable antiarrhythmic profile.