Selective noradrenaline reuptake inhibitor atomoxetine directly blocks hERG currents

Atomoxetine is a selective noradrenaline reuptake inhibitor, recently approved for the treatment of attention-deficit/hyperactivity disorder. So far, atomoxetine has been shown to be well tolerated, and cardiovascular effects were found to be negligible. However, two independent cases of QT interval prolongation, associated with atomoxetine overdose, have been reported recently. We therefore analysed acute and subacute effects of atomoxetine on cloned human Ether-à-Go-Go-Related Gene (hERG) channels. Experimental approach: hERG channels were heterologously expressed in Xenopus oocytes and in a human embryonic kidney cell line and hERG currents were measured using voltage clamp and patch clamp techniques. Action potential recordings were made in isolated guinea-pig cardiomyocytes. Gene expression and channel surface expression were analysed using quantitative reverse transcriptase polymerase chain reaction, Western blot and the patch clamp techniques. Key

Atomoxetine is a selective noradrenaline reuptake inhibitor, recently approved for the treatment of attention-deficit/hyperactivity disorder. So far, atomoxetine has been shown to be well tolerated, and cardiovascular effects were found to be negligible. However, two independent cases of QT interval prolongation, associated with atomoxetine overdose, have been reported recently. We therefore analysed acute and subacute effects of atomoxetine on cloned human Ether-à-Go-Go-Related Gene (hERG) channels. Experimental approach: hERG channels were heterologously expressed in Xenopus oocytes and in a human embryonic kidney cell line and hERG currents were measured using voltage clamp and patch clamp techniques. Action potential recordings were made in isolated guinea-pig cardiomyocytes. Gene expression and channel surface expression were analysed using quantitative reverse transcriptase polymerase chain reaction, Western blot and the patch clamp techniques. Key

In human embryonic kidney cells, atomoxetine inhibited hERG current with an IC(50) of 6.3 micromol.L(-1). Development of block and washout were fast. Channel activation and inactivation were not affected. Inhibition was state-dependent, suggesting an open channel block. No use-dependence was observed. Inhibitory effects of atomoxetine were attenuated in the pore mutants Y652A and F656A. In guinea-pig cardiomyocytes, atomoxetine lengthened action potential duration without inducing action potential triangulation. Overnight incubation with high atomoxetine concentrations resulted in a decrease of channel surface expression. Conclusions and implications: Whereas subacute effects of atomoxetine seem negligible under therapeutically relevant concentrations, hERG channel block should be considered in cases of atomoxetine overdose and when administering atomoxetine to patients at increased risk for the development of acquired long-QT syndrome.