The Antidepressant Paroxetine Reduces the Cardiac Sodium Current

Abstract

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 (NaV1.5) 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 NaV1.5 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 NaV1.5 current. We found that paroxetine led to a decrease in peak NaV1.5 current in a concentration-dependent manner with an IC50 of 6.8 ± 1.1 µM. In addition, paroxetine caused a significant hyperpolarizing shift in the steady-state inactivation of the NaV1.5 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 NaV1.5 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 NaV1.5 encoding SCN5A gene. In conclusion, paroxetine acts as an inhibitor of NaV1.5 channels, which may enhance the effects of loss-of-function mutations in SCN5A.

Bidirectional associations between mental disorders, antidepressants and cardiovascular disease

“…Specifically, paroxetine, an SSRI, significantly diminishes the rapid sodium flow in cardiomyocytes located in the human left ventricle. This results in the deceleration of conduction and a decrease in excitability, particularly when a loss-of-function mutation in the SCN5A gene is present 30…”

“…This results in the deceleration of conduction and a decrease in excitability, particularly when a loss-of-function mutation in the SCN5A gene is present. 30 …”

The opioid tramadol blocks the cardiac sodium channel Nav1.5 in HEK293 cells

“…This may be due to the different experiment conditions, such as measurement temperature, the sodium and fluoride concentrations of the used solutions, or the different cell models. 20 , 43–45 Even so, at clinically relevant high concentrations, tramadol-induced overdose toxicity still may be achieved in clinical cases. For instance, the tramadol concentrations in peripheral blood were reported from 1.6 mg/L (6.1 μ m ) to 15.1 mg/L (57.3 μ m ) in an overview report, which is close to our measured IC 50 of Na v 1.5 channels in a partially fast-inactivated or slow-inactivated state.…”

“…This is increasingly recognized for a growing number of noncardiac drugs. 7 At present, this group contains tricyclic antidepressants 19 , 20 and antiepileptic drugs. 21 We hypothesize that this group may also contain opioids and opioid agonists.…”

Role of Pharmacokinetics and Pharmacogenetics of Antidepressant-Induced Prolongation of the QT Interval and Torsade de Pointes in Patients with Mental Disorders

“…Sertraline, citalopram, and escitalopram do not block sodium channels, unlike fluvoxamine, fluoxetine, and paroxetine, which block them [65]. Paroxetine significantly reduces the rapid current of sodium ions through the membrane of human left ventricular cardiomyocytes due to the inhibition of Nav1.5 channels, which leads to a slowdown in conduction and a decrease in the excitability of cardiomyocytes [92].…”