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 (I _NCX) in guinea pig cardiac ventricular cells. The I _NCX 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 μM), was used to completely inhibit I _NCX. Dronedarone inhibited I _NCX in a concentration-dependent manner. The IC₅₀ values for the outward and inward I _NCX inhibition were about 33 and 28 μM, respectively, with the Hill coefficient of 1 for both. The inhibitory effect of dronedarone at 50 μM on I _NCX 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 I _NCX but the potency is tenfold less than that of amiodarone. Dronedarone may modestly inhibit I _NCX in a therapeutic concentration range.