The Antidepressant Paroxetine Reduces the Cardiac Sodium Current

• Published in: International journal of molecular sciences 2023-01, Vol.24 (3), p.1904
• Main Authors: Plijter, Ingmar S, Verkerk, Arie O, Wilders, Ronald
• Format: Article
• Language: English
• Subjects: Action potential; Action Potentials; Animals; antidepressant drugs; Antidepressants; Antidepressive Agents - pharmacology; Cardiomyocytes; cellular electrophysiology; Channel gating; Conduction; Drug dosages; HEK293 Cells; Humans; Long QT syndrome; Mathematical models; Mutation; Myocytes, Cardiac - metabolism; NaV1.5 channels; NAV1.5 Voltage-Gated Sodium Channel - genetics; Paroxetine; Paroxetine - pharmacology; patch clamp recordings; Patients; Rabbits; Sodium; Sodium - metabolism; Sodium channels (voltage-gated); sodium current; Ventricle
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24031904

A considerable amount of literature has been published on antidepressants and cardiac ion channel dysfunction. The antidepressant paroxetine has been associated with Brugada syndrome and long QT syndrome, albeit on the basis of conflicting findings. The cardiac voltage-gated sodium channel (Na 1.5) is related to both of these syndromes, suggesting that paroxetine may have an effect on this channel. In the present study, we therefore carried out patch clamp experiments to examine the effect of paroxetine on human Na 1.5 channels stably expressed in human embryonic kidney 293 (HEK-293) cells as well as on action potentials of isolated rabbit left ventricular cardiomyocytes. Additionally, computer simulations were conducted to test the functional effects of the experimentally observed paroxetine-induced changes in the Na 1.5 current. We found that paroxetine led to a decrease in peak Na 1.5 current in a concentration-dependent manner with an IC of 6.8 ± 1.1 µM. In addition, paroxetine caused a significant hyperpolarizing shift in the steady-state inactivation of the Na 1.5 current as well as a significant increase in its rate of inactivation. Paroxetine (3 µM) affected the action potential of the left ventricular cardiomyocytes, significantly decreasing its maximum upstroke velocity and amplitude, both of which are mainly regulated by the Na 1.5 current. Our computer simulations demonstrated that paroxetine substantially reduces the fast sodium current of human left ventricular cardiomyocytes, thereby slowing conduction and reducing excitability in strands of cells, in particular if conduction and excitability are already inhibited by a loss-of-function mutation in the Na 1.5 encoding gene. In conclusion, paroxetine acts as an inhibitor of Na 1.5 channels, which may enhance the effects of loss-of-function mutations in .