Abstract
Atomoxetine, a neuroactive drug, is approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). It is primarily known as a high affinity blocker of the noradrenaline transporter, whereby its application leads to an increased level of the corresponding neurotransmitter in different brain regions. However, the concentrations used to obtain clinical effects are much higher than those which are required to block the transporter system. Thus, off-target effects are likely to occur. In this way, we previously identified atomoxetine as blocker of NMDA receptors. As many psychotropic drugs give rise to sudden death of cardiac origin, we now tested the hypothesis whether atomoxetine also interacts with voltage-gated sodium channels of heart muscle type in clinically relevant concentrations. Electrophysiological experiments were performed by means of the patch-clamp technique at human heart muscle sodium channels (hNav1.5) heterogeneously expressed in human embryonic kidney cells. Atomoxetine inhibited sodium channels in a state- and use-dependent manner. Atomoxetine had only a weak affinity for the resting state of the hNav1.5 (Kr: ∼ 120 µM). The efficacy of atomoxetine strongly increased with membrane depolarization, indicating that the inactivated state is an important target. A hallmark of this drug was its slow interaction. By use of different experimental settings, we concluded that the interaction occurs with the slow inactivated state as well as by slow kinetics with the fast-inactivated state. Half-maximal effective concentrations (2–3 µM) were well within the concentration range found in plasma of treated patients. Atomoxetine also interacted with the open channel. However, the interaction was not fast enough to accelerate the time constant of fast inactivation. Nevertheless, when using the inactivation-deficient hNav1.5_I408W_L409C_A410W mutant, we found that the persistent late current was blocked half maximal at about 3 µM atomoxetine. The interaction most probably occurred via the local anesthetic binding site. Atomoxetine inhibited sodium channels at a similar concentration as it is used for the treatment of ADHD. Due to its slow interaction and by inhibiting the late current, it potentially exerts antiarrhythmic properties.
Highlights
Atomoxetine belongs to the group of norepinephrine transporter (NET) inhibitors
We investigated if and how atomoxetine interacts with voltage-gated sodium channels (VGSCs)
When the perfusion was switched to 3 μM atomoxetine the current amplitude instantaneously dropped to a new value and stayed almost constant upon ongoing activations in the presence of atomoxetine (Figure 1)
Summary
Atomoxetine belongs to the group of norepinephrine transporter (NET) inhibitors. It is the first nonstimulant compound licensed for the treatment of attention-deficit/hyperactivity disorder (ADHD) (Peterson et al, 2008). Increased intrasynaptic norepinephrine (NE) levels are detectable shortly after oral application of low doses of atomoxetine (Takano et al, 2009). Using clinically relevant concentrations of atomoxetine we and others found further interactions with different ion channels (Scherer et al, 2009; Ludolph et al, 2010). A similar behaviour is known for other neuroactive drugs which in therapeutic relevant concentrations do not solely interact with their main target and with ion channels, predominantly with ligand gated ion channels (Lenkey et al, 2006). We investigated whether atomoxetine interacts with voltage-gated sodium channels (VGSCs)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have