Multiple Mechanisms Contribute to Cardiotoxicity Observed with the Antidepressant Desipramine

The cardiotoxicity of antidepressants is well recognized. Common electrocardiographic changes precipitated in particular by an overdose include QRS widening as well as prolongation of the QT interval and torsade de pointes tachycardia. QT prolongation by antidepressants has usually been associated with acute block of hERG/IKr currents. This study has been designed to provide a more complete picture of the molecular mechanisms underlying cardiac side effects induced by the antidepressant desipramine. We have studied acute block in HEK/hERG WT cells using patch-clamp recordings and found that desipramine reduced hERG currents with an IC50 value of 11.9μM. In HEK/hERG F656V, a mutation that reduces drug binding, hERG currents were blocked half-maximally with 48.3μM. We used Western blots to monitor the effects of desipramine on hERG trafficking. In these experiments we found that the fully-glycosylated cell surface form of hERG was reduced with an IC50 of 5.1μM on overnight incubation. When long-term effects were studied using electrophysiological current recordings, hERG tail currents were decreased with an IC50 of 7.5μM. Accordingly, hERG surface expression was reduced by desipramine when monitored directly using a cell-based assay (IC50, 17.3μM) or confocal imaging. Importantly, the reduction in surface expression was not attenuated by mutation of residue F656 in the drug binding site of hERG. In guinea pig ventricular myocytes action potential duration was prolonged in a dose-dependent manner as expected on acute desipramine exposure. However, long-term exposure increased action potential duration only marginally. Finally, desipramine triggered apoptosis in cells expressing hERG channels. Taken together, desipramine exerts adverse cardiac effects by at least three different mechanisms: (1) direct hERG channel block, (2) disruption of hERG trafficking, and (3) induction of apoptosis.