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] /= 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.

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The aim of this study was to investigate the mechanism of cellular regulation of mitochondrial respiration in permeabilized cardiac cells with clearly different structural organization: (i) in isolated rat cardiomyocytes with very regular mitochondrial arrangement, (ii) in HL-1 cells from mouse heart, and (iii) in non-beating (NB HL-1 cells) without sarcomeres with irregular and dynamic filamentous mitochondrial network. We found striking differences in the kinetics of respiration regulation by exogenous ADP between these cells: the apparent Km for exogenous ADP was by more than order of magnitude (14 times) lower in the permeabilized non-beating NB HL-1 cells without sarcomeres (25+/-4 microM) and seven times lower in normally cultured HL-1 cells (47+/-15 microM) than in permeabilized primary cardiomyocytes (360+/-51 microM). In the latter cells, treatment with trypsin resulted in dramatic changes in intracellular structure that were associated with 3-fold decrease in apparent Km for ADP in regulation of respiration. In contrast to permeabilized cardiomyocytes, in NB HL-1 cells creatine kinase activity was low and the endogenous ADP fluxes from MgATPases recorded spectrophotometrically by the coupled enzyme assay were not reduced after activation of mitochondrial oxidative phosphorylation by the addition of mitochondrial substrates, showing the absence of ADP channelling in the NB HL-1 cells. While in the permeabilized cardiomyocytes creatine strongly activated mitochondrial respiration even in the presence of powerful competing pyruvate kinase-phosphoenolpyruvate system, in the NB HL-1 cells the stimulatory effect of creatine was not significant. The results of this study show that in normal adult cardiomyocytes and HL-1 cells intracellular local restrictions of diffusion of adenine nucleotides and metabolic feedback regulation of respiration via phosphotransfer networks are different, most probably related to differences in structural organization of these cells.