title: Acute inhibitory effect of dronedarone, a noniodinated benzofuran analogue of amiodarone, on Na+/Ca2+ exchange current in guinea pig cardiac ventricular myocytes.
abstract: Using the whole-cell voltage-clamp method, we examined an acute effect of dronedarone, a noniodinated benzofuran analogue of amiodarone, on Na+/Ca2+ exchange current (INCX) in guinea pig cardiac ventricular cells. The INCX was recorded by ramp pulses with a holding potential of -60 mV using a pipette solution containing 226 nM free Ca2+ (20 mM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid and 10 mM Ca2+) and 20 mM Na+. The external solution contained 140 mM Na+, 1 mM Ca2+, and blockers of other currents and pumps such as Cs+, nifedipine, ryanodine, and ouabain. A selective potent NCX inhibitor, KB-R7943 (100 microM), was used to completely inhibit INCX. Dronedarone inhibited INCX in a concentration-dependent manner. The IC50 values for the outward and inward INCX inhibition were about 33 and 28 microM, respectively, with the Hill coefficient of 1 for both. The inhibitory effect of dronedarone at 50 microM on INCX did not change in the presence of trypsin in the pipette solution. Therefore, dronedarone is classified as a trypsin-insensitive NCX inhibitor and distinct from amiodarone which is a trypsin sensitive. We conclude that dronedarone inhibits INCX but the potency is tenfold less than that of amiodarone. Dronedarone may modestly inhibit INCX in a therapeutic concentration range.
authors.affiliation: Division of Pharmacological Science, Department of Health Science, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu, 431-3192, Japan. w-yasu@hama-med.ac.jp
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Junko
authors.initials: J
authors.lastname: Kimura
mesh_terms: D000638:Amiodarone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000077764:Dronedarone; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D020128:Inhibitory Concentration 50; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014357:Trypsin / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D019831:Sodium-Calcium Exchanger; D014357:Trypsin; D000077764:Dronedarone; D000638:Amiodarone