Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone

Varró, András and Takács, János and Németh, Miklós and Hála, Ottó and Virág, László and Iost, Norbert and Baláti, Beáta and Ágoston, Márta and Vereckei, András and Pastor, Gilbert and Delbruyère, Martine and Gautier, Patrick and Nisato, Dino and Papp, Julius Gyula (2001) Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone. British Journal of Pharmacology, 133 (5). pp. 625-634. ISSN 0007-1188

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Abstract

1 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. 2 Chronic treatment with dronedarone (2 x 25 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 electocardiogram 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. 3 Acute superfusion of dronedarone (10 muM), similar to that of amiodarone (10 muM), 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 nz from 309.6 +/- 11.8 to 287.1 +/- 10.8 ms, n=7, P < 0.05). 4 Both dronedarone (10 muM) and amiodarone (10 muM) superfusion reduced the incidence of early and delayed afterdepolarizations evoked by 1 muM dofetilide and 0.2 muM strophantidine in Purkinje fibres. 5 In patch-clamp experiments 10 muM dronedarone markedly reduced the L-type calcium current (76.5 +/- 10.7 %, 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. 6 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.

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