Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone.
The electrophysiological effects of dronedarone, a new nonionidated analogue of amiodarone were studied after chronic and acute administration in dog Purkinje fibres, papillary muscle and isolated ventricular myocytes, and compared with those of amiodarone by applying conventional microelectrode and patch-clamp techniques. Chronic treatment with dronedarone (2x25 mg(-1) kg(-1) day p.o. for 4 weeks), unlike chronic administration of amiodarone (50 mg(-1) kg(-1) day p.o. for 4 weeks), did not lengthen significantly the QTc interval of the electrocardiogram or the action potential duration (APD) in papillary muscle. After chronic oral treatment with dronedarone a small, but significant use-dependent V(max) block was noticed, while after chronic amiodarone administration a strong use-dependent V(max) depression was observed. Acute superfusion of dronedarone (10 microM), similar to that of amiodarone (10 microM), moderately lengthened APD in papillary muscle (at 1 Hz from 239.6+/-5.3 to 248.6+/-5.3 ms, n=13, P<0.05), but shortened it in Purkinje fibres (at 1 Hz from 309.6+/-11.8 to 287.1+/-10.8 ms, n=7, P<0.05). Both dronedarone (10 microM) and amiodarone (10 microM) superfusion reduced the incidence of early and delayed afterdepolarizations evoked by 1 microM dofetilide and 0.2 microM strophantidine in Purkinje fibres. In patch-clamp experiments 10 microM dronedarone markedly reduced the L-type calcium current (76.5+/-0.7 %, n=6, P<0.05) and the rapid component of the delayed rectifier potassium current (97+/-1.2 %, n=5, P<0.05) in ventricular myocytes. It is concluded that after acute administration dronedarone exhibits effects on cardiac electrical activity similar to those of amiodarone, but it lacks the 'amiodarone like' chronic electrophysiological characteristics.
Varró
A
A
Department of Pharmacology & Pharmacotherapy, Faculty of Medicine, University of Szeged, Dóm tér 12, H-6701 Szeged, Hungary.
Takács
J
J
Németh
M
M
Hála
O
O
Virág
L
L
Iost
N
N
Baláti
B
B
Agoston
M
M
Vereckei
A
A
Pastor
G
G
Delbruyère
M
M
Gautier
P
P
Nisato
D
D
Papp
J G
JG
D000200:Action Potentials / Q000187:drug effects; D000638:Amiodarone / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004285:Dogs; D000077764:Dronedarone; D004558:Electric Stimulation; D004562:Electrocardiography; D004594:Electrophysiology; D005260:Female; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*; D016276:Ventricular Function
D014665:Vasodilator Agents; D000077764:Dronedarone; C036116:desethylamiodarone; D000638:Amiodarone