(Circulation. 1999;100:2276.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Electrophysiological Effects of Dronedarone (SR33589), a Noniodinated Benzofuran Derivative, in the Rabbit Heart
Comparison With Amiodarone
From the Cardiovascular Research Laboratory, Section of Cardiology, VA Medical Center of West Los Angeles and UCLA School of Medicine, Los Angeles, Calif.
Correspondence to Bramah N. Singh, MD, Section of Cardiology, 111E, VA Medical Center of West Los Angeles, 11301 Wilshire Blvd, Los Angeles, CA 90073.
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% (APD50) and 90% (APD90) repolarization and upstroke dV/dt (Vmax) 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 APD50 and APD90 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). Vmax 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.
Key Words: potentials • amiodarone • dronedarone • electrophysiology • drugs
This article has been cited by other articles:
 |
|
 |
|
  R. A. Kloner A Salute to Our Founding Editor-in-Chief Bramah N. Singh, MD, DPhil, DSc, FRCP Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2009; 14(3): 154 - 156. [PDF]
|
|
|
|
 |
|
 C. Patel, G.-X. Yan, and P. R. Kowey Dronedarone Circulation, August 18, 2009; 120(7): 636 - 644. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Hohnloser, H. J.G.M. Crijns, M. van Eickels, C. Gaudin, R. L. Page, C. Torp-Pedersen, S. J. Connolly, and the ATHENA Investigators Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation N. Engl. J. Med., February 12, 2009; 360(7): 668 - 678. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. N. Singh, S. J. Connolly, H. J.G.M. Crijns, D. Roy, P. R. Kowey, A. Capucci, D. Radzik, E. M. Aliot, S. H. Hohnloser, and the EURIDIS and ADONIS Investigators Dronedarone for Maintenance of Sinus Rhythm in Atrial Fibrillation or Flutter N. Engl. J. Med., September 6, 2007; 357(10): 987 - 999. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Celestino, E. Medei, S. Moro, M. V. Elizari, and S. Sicouri Acute In Vitro Effects of Dronedarone, an Iodine-Free Derivative, and Amiodarone, on the Rabbit Sinoatrial Node Automaticity: A Comparative Study Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2007; 12(3): 248 - 257. [Abstract] [PDF]
|
|
|
|
 |
|
 B. N. Singh and E. Aliot Newer antiarrhythmic agents for maintaining sinus rhythm in atrial fibrillation: simplicity or complexity? Eur. Heart J. Suppl., September 1, 2007; 9(suppl_G): G17 - G25. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M Dale and C M. White Dronedarone: An Amiodarone Analog for the Treatment of Atrial Fibrillation and Atrial Flutter Ann. Pharmacother., April 1, 2007; 41(4): 599 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Tafreshi and J. Rowles A Review of the Investigational Antiarrhythmic Agent Dronedarone Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2007; 12(1): 15 - 26. [Abstract] [PDF]
|
|
|
|
|
|
N. Wadhani, J. S. Sarma, B. N. Singh, D. Radzik, and C. Gaud Dose-Dependent Effects of Oral Dronedarone on the Circadian Variation of RR and QT Intervals in Healthy Subjects: Implications for Antiarrhythmic Actions. Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2006; 11(3): 184 - 190. [Abstract] [PDF]
|
|
|
|
 |
|
 Writing Committee Members, V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 651 - 745. [Full Text] [PDF]
|
|
|
|
 |
|
 V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society J. Am. Coll. Cardiol., August 15, 2006; 48(4): e149 - e246. [Full Text] [PDF]
|
|
|
|
|
|
V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society Circulation, August 15, 2006; 114(7): e257 - e354. [Full Text] [PDF]
|
|
|
|
|
|
S. Le Bouter, A. El Harchi, C. Marionneau, C. Bellocq, A. Chambellan, T. van Veen, C. Boixel, B. Gavillet, H. Abriel, K. Le Quang, et al. Long-Term Amiodarone Administration Remodels Expression of Ion Channel Transcripts in the Mouse Heart Circulation, November 9, 2004; 110(19): 3028 - 3035. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. N. Singh and N. Wadhani Antiarrhythmic and Proarrhythmic Properties of QT-Prolonging Antianginal Drugs Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2004; 9(1_suppl): S85 - S97. [Abstract] [PDF]
|
|
|
|
 |
|
 P. Touboul, J. Brugada, A. Capucci, H. J.G.M. Crijns, N. Edvardsson, and S. H. Hohnloser Dronedarone for prevention of atrial fibrillation: A dose-ranging study Eur. Heart J., August 2, 2003; 24(16): 1481 - 1487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. N. Singh Atrial Fibrillation: Epidemiologic Considerations and Rationale for Conversion and Maintenance of Sinus Rhythm Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2003; 8(1_suppl): S13 - S26. [Abstract] [PDF]
|
|
|
|
 |
|
 H. C. van Beeren, W. M. C. Jong, E. Kaptein, T. J. Visser, O. Bakker, and W. M. Wiersinga Dronerarone Acts as a Selective Inhibitor of 3,5,3'-Triiodothyronine Binding to Thyroid Hormone Receptor-{alpha}1: In Vitro and in Vivo Evidence Endocrinology, February 1, 2003; 144(2): 552 - 558. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D Pitt, C. Fernandes, N. L Bewick, P. D Hemsworth, K. A Buhagiar, P. S Hansen, H. H Rasmussen, L. Delbridge, and D. W Whalley Chronic amiodarone-induced inhibition of the Na+-K+ pump in rabbit cardiac myocytes is thyroid-dependent: comparison with dronedarone Cardiovasc Res, January 1, 2003; 57(1): 101 - 108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Khairy and S. Nattel New insights into the mechanisms and management of atrial fibrillation Can. Med. Assoc. J., October 29, 2002; 167(9): 1012 - 1020. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-E. Chiang, H.-N. Luk, T.-M. Wang, and P. Y.-A. Ding Effects of sildenafil on cardiac repolarization Cardiovasc Res, August 1, 2002; 55(2): 290 - 299. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. van Opstal, M. Schoenmakers, S. C. Verduyn, S.H. M. de Groot, J. D.M. Leunissen, F. F. van der Hulst, M. M.C. Molenschot, H. J.J. Wellens, and M. A. Vos Chronic Amiodarone Evokes No Torsade de Pointes Arrhythmias Despite QT Lengthening in an Animal Model of Acquired Long-QT Syndrome Circulation, November 27, 2001; 104(22): 2722 - 2727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. N. Singh and J. S. M. Sarma Mechanisms of Action of Antiarrhythmic Drugs Relative to the Origin and Perpetuation of Cardiac Arrhythmias Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2001; 6(1): 69 - 87. [PDF]
|
|
|
|
 |
|
 M. J. P. Raatikainen, T. E. Morey, P. Druzgala, P. Milner, M. D. Gonzalez, and D. M. Dennis Potent and Reversible Effects of ATI-2001 on Atrial and Atrioventricular Nodal Electrophysiological Properties in Guinea Pig Isolated Perfused Heart J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 779 - 785. [Abstract] [Full Text]
|
|
|
|
|
|
S. K. Doshi and B. N. Singh Reviews: Pure Class III Antiarrhythmic Drugs: Focus on Dofetilide Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(4): 237 - 247. [PDF]
|
|