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 (nϭ7 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 (nϭ5) at various concentrations of SR (0 to 10 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 lengths were compared by ANOVA with repeated measures. Compared with control, AM and SR increased RR, QT, and QTc intervals (PϽ0.0001 for all). Ventricular APD 50 and APD 90 were lengthened by 20% to 49% as a function of dose (PϽ0.005 to Ͻ0.0001) and cycle length (PϽ0.001). SR100 effects were greater than those of AM100 (PϽ0.002). V max was decreased by both AM100 (PϽ0.0001) and SR100 (PϽ0.01). Sinoatrial node automaticity was slowed in treated groups compared with that of the control group (PϽ0.0001 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. (Circulation. 1999;100:2276-2281.)

Pharmacologic Management of Atrial Fibrillation: Established and Emerging Options

“…39,40 The chemical structure of dronedarone differs from that of amiodarone in its lack of iodine, which could minimize the impact of dronedarone on thyroid function. The lack of iodine also could make dronedarone less lipophilic and limit its distribution and potential for extracardiac toxicities.…”

Topics on the Na+/Ca2+ Exchanger: Pharmacological Characterization of Na+/Ca2+ Exchanger Inhibitors

“…3), a new non-iodinated benzofuran analogue of amiodarone, is similar to amiodarone analogues in electrophysiological studies (39). Dronedarone possesses antiarrhythmic activity like amiodarone in the hearts of dogs and rats (40,41).…”

Long-Term Amiodarone Administration Remodels Expression of Ion Channel Transcripts in the Mouse Heart

“…17 The small but significant increase in corrected QT at the highest dose of amiodarone is also consistent with the 5% to 18% increase obtained in different animal models treated orally for the same period of time. 18,19 In humans, the prolongation of repolarization rarely exceeds 10% to 15%, as assessed with surface ECG 20 or monophasic action potential (MAP) recording. 21,22 Early on, Drvota and coworkers 4 performed in vitro experiments suggesting that the effects of DEA on cardiac electrical activity could depend on gene expression.…”