Electrophysiological effects of dronedarone (SR33589), a noniodinated benzofuran derivative, in the rabbit heart - Comparison with amiodarone

Background-To overcome the side effects of amiodarone (AM), its noniodinate d analogue, dronedarone (SR), was synthesized. In this study, its electroph ysiological effects were compared with those of AM in rabbit hearts. Methods and Results-Five animal groups (n=7 each) for 3 weeks received dail y 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 ef fects were studied in controls (n=5) at various concentrations of SR (0 to 10 mu mol/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 l engths were compared by ANOVA with repeated measures. Compared with control , AM and SR increased RR, QT, and QTc intervals (P<0.0001 for all). Ventric ular APD(50) and APD(90) were lengthened by 20% to 49% as a function of dos e (P<0.005 to <0.0001) and cycle length (P<0.001). SR100 effects were great er than those of AM100 (P<0.002). V-max was decreased by both AM100 (P<0.00 01) 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.