Electrophysiological Effects of Dronedarone (SR33589), a Noniodinated Benzofuran Derivative, in the Rabbit Heart

Abstract

Background —To overcome the side effects of amiodarone (AM), its noniodinated analogue, dronedarone (SR), was synthesized. In this study, its electrophysiological effects were compared with those of AM in rabbit hearts. Methods and Results —Five animal groups (n=7 each) for 3 weeks received daily oral treatment of 1 of these regimens: (1) control, vehicle only; (2) AM 50 mg/kg (AM50); (3) AM 100 mg/kg (AM100); (4) SR 50 mg/kg (SR50); and (5) SR 100 mg/kg (SR100). ECGs were recorded before drug and at 3 weeks of drug before euthanasia. Action potentials were recorded from isolated papillary muscle and sinoatrial node by microelectrode techniques. The short-term effects were studied in controls (n=5) at various concentrations of SR (0 to 10 μmol/L) in tissue bath. Action potential duration at 50% (APD 50 ) and 90% (APD 90 ) repolarization and upstroke dV/dt (V max ) at various cycle lengths were compared by ANOVA with repeated measures. Compared with control, AM and SR increased RR, QT, and QTc intervals ( P <0.0001 for all). Ventricular APD 50 and APD 90 were lengthened by 20% to 49% as a function of dose ( P <0.005 to <0.0001) and cycle length ( P <0.001). SR100 effects were greater than those of AM100 ( P <0.002). V max was decreased by both AM100 ( P <0.0001) and SR100 ( P <0.01). Sinoatrial node automaticity was slowed in treated groups compared with that of the control group ( P <0.0001 for all). Conclusions —The electrophysiological effects of dronedarone are similar to those of AM but more potent, despite deletion of iodine from its molecular structure, a finding of importance for the development of future class III antiarrhythmic compounds.