The Antidepressant Paroxetine Reduces the Cardiac Sodium Current
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<su...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/3/1904 |
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| author | Ingmar S. Plijter Arie O. Verkerk Ronald Wilders |
| author_facet | Ingmar S. Plijter Arie O. Verkerk Ronald Wilders |
| author_sort | Ingmar S. Plijter |
| collection | DOAJ |
| description | 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<sub>V</sub>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<sub>V</sub>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<sub>V</sub>1.5 current. We found that paroxetine led to a decrease in peak Na<sub>V</sub>1.5 current in a concentration-dependent manner with an IC<sub>50</sub> of 6.8 ± 1.1 µM. In addition, paroxetine caused a significant hyperpolarizing shift in the steady-state inactivation of the Na<sub>V</sub>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<sub>V</sub>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<sub>V</sub>1.5 encoding <i>SCN5A</i> gene. In conclusion, paroxetine acts as an inhibitor of Na<sub>V</sub>1.5 channels, which may enhance the effects of loss-of-function mutations in <i>SCN5A</i>. |
| first_indexed | 2024-03-11T09:42:47Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:42:47Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5cbeabfafe0f4bd3b73d821500c257432023-11-16T16:49:30ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01243190410.3390/ijms24031904The Antidepressant Paroxetine Reduces the Cardiac Sodium CurrentIngmar S. Plijter0Arie O. Verkerk1Ronald Wilders2Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDepartment of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDepartment of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsA 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<sub>V</sub>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<sub>V</sub>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<sub>V</sub>1.5 current. We found that paroxetine led to a decrease in peak Na<sub>V</sub>1.5 current in a concentration-dependent manner with an IC<sub>50</sub> of 6.8 ± 1.1 µM. In addition, paroxetine caused a significant hyperpolarizing shift in the steady-state inactivation of the Na<sub>V</sub>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<sub>V</sub>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<sub>V</sub>1.5 encoding <i>SCN5A</i> gene. In conclusion, paroxetine acts as an inhibitor of Na<sub>V</sub>1.5 channels, which may enhance the effects of loss-of-function mutations in <i>SCN5A</i>.https://www.mdpi.com/1422-0067/24/3/1904antidepressant drugsNa<sub>V</sub>1.5 channelssodium currentaction potentialcellular electrophysiologypatch clamp recordings |
| spellingShingle | Ingmar S. Plijter Arie O. Verkerk Ronald Wilders The Antidepressant Paroxetine Reduces the Cardiac Sodium Current International Journal of Molecular Sciences antidepressant drugs Na<sub>V</sub>1.5 channels sodium current action potential cellular electrophysiology patch clamp recordings |
| title | The Antidepressant Paroxetine Reduces the Cardiac Sodium Current |
| title_full | The Antidepressant Paroxetine Reduces the Cardiac Sodium Current |
| title_fullStr | The Antidepressant Paroxetine Reduces the Cardiac Sodium Current |
| title_full_unstemmed | The Antidepressant Paroxetine Reduces the Cardiac Sodium Current |
| title_short | The Antidepressant Paroxetine Reduces the Cardiac Sodium Current |
| title_sort | antidepressant paroxetine reduces the cardiac sodium current |
| topic | antidepressant drugs Na<sub>V</sub>1.5 channels sodium current action potential cellular electrophysiology patch clamp recordings |
| url | https://www.mdpi.com/1422-0067/24/3/1904 |
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