Electrophysiologic characterization of dronedarone in guinea pig ventricular cells.
The electrophysiological properties of dronedarone (SR33589), a noniodinated amiodarone-like agent, were studied on action potential (AP) and contraction of papillary muscle and on membrane ionic currents, Ca2+ transient, and shortening of ventricular cells of the guinea pig heart. In multicellular preparations, dronedarone (3, 10, and 30 microM) decreased maximum rate of rise of AP (dV/dt max) with a concentration- and frequency-dependent relationship; resting potential was not modified and AP amplitude was decreased only at 30 microM. The effects of dronedarone on AP durations (APDs) at different percentages of repolarization were not significantly changed, except for a slight decrease in APD30 and APD50 at the highest concentration. In isolated ventricular myocytes, dronedarone inhibited rapidly activating delayed-rectifier K+ current (I(Kr)) (median inhibitory concentration [IC50] </= 3 microM voltage-independent); slowly activating delayed-rectifier K+ current (I(Ks)) (IC50 approximately/= 10 microM voltage-dependent and time-, frequency-, or use-independent); and inward rectifier potassium current (I(K1)) (IC50 >/= 30 microM). Dronedarone blocked L-type Ca2+ current (I(Ca(L))) (IC50 = 0.18 +/- 0.018 microM at a stimulation frequency of 0.033 Hz) in a use- and frequency-dependent manner. Simultaneously to these electrophysiological effects, dronedarone reduced contraction amplitudes of papillary muscle and decreased Ca2+ transient and shortening of ventricular myocytes. The results show that dronedarone is a multichannel blocker because it decreases dV/dt max (I(Na)), I(Ca(L)), I(Kr), I(Ks), and I(K1). These effects are accompanied by a reduction in free intracellular calcium and contraction amplitudes. Dronedarone does not significantly change APD whatever the stimulation frequency. Our data demonstrate that the acute electrophysiological characteristics of dronedarone, despite absence of iodine in its molecular structure, are very similar to those of amiodarone in cardiac ventricle.
Gautier
Patrick
P
Sanofi-Synthélabo Recherche, Cardiovascular/Thrombosis Research Department, 371, rue du Professeur Joseph Blayac, 34184 Montpellier Cedex 04, France. patrick.gautier@sanofi-synthelabo.com
Guillemare
Eric
E
Marion
Aline
A
Bertrand
Jean-Philippe
JP
Tourneur
Yves
Y
Nisato
Dino
D
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000638:Amiodarone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000077764:Dronedarone; D004594:Electrophysiology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D016276:Ventricular Function
D020746:Calcium Channels, L-Type; D000077764:Dronedarone; D000638:Amiodarone