Fluoxetine Blocks Nav1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics

Abstract

The voltage-gated Na v 1.5 channel is essential for the propagation of action potentials in the heart. Malfunctions of this channel are known to cause hereditary diseases. It is a prime target for class 1 antiarrhythmic drugs and a number of antidepressants. Our study investigated the Na v 1.5 blocking properties of fluoxetine, a selective serotonin reuptake inhibitor. Na v 1.5 channels were expressed in HEK-293 cells, and Na 1 currents were recorded using the patch-clamp technique. Dose-response curves of racemic fluoxetine (IC 50 5 39 mM) and its optical isomers had a similar IC 50 [40 and 47 mM for the (1) and (2) isomers, respectively]. Norfluoxetine, a fluoxetine metabolite, had a higher affinity than fluoxetine, with an IC 50 of 29 mM. Fluoxetine inhibited currents in a frequency-dependent manner, shifted steady-state inactivation to more hyperpolarized potentials, and slowed the recovery of Na v 1.5 from inactivation. Mutating a phenylalanine (F1760) and a tyrosine (Y1767) in the S6 segment of domain (D) IV (DIVS6) significantly reduced the affinity of fluoxetine and its frequency-dependent inhibition. We used a noninactivating Na v 1.5 mutant to show that fluoxetine displays open-channel block behavior. The molecular model of fluoxetine in Na v 1.5 was in agreement with mutational experiments in which F1760 and Y1767 were found to be the key residues in binding fluoxetine. We concluded that fluoxetine blocks Na v 1.5 by binding to the class 1 antiarrhythmic site. The blocking of cardiac Na 1 channels should be taken into consideration when prescribing fluoxetine alone or in association with other drugs that may be cardiotoxic or for patients with conduction disorders.

Modeling the human Na_v1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

“…Another model, which focused on the pore-forming region ( Figures S5 and S6 ) and the short pore helices of hNa v 1.5, was developed by Poulin et al and aimed at studying the interaction of a small number of drugs (eg, fluoxetine) with hNa v 1.5. 12 In Poulin et al’s model, the extracellular linkers of the P-loops were truncated to match the length of the crystallized bacterial channel. The model was also optimized in implicit solvent without lipid molecules.…”

Differential modulation of Nav1.7 and Nav1.8 channels by antidepressant drugs

“…This effect may reduce firing by sensory neurons. While Na + channel blockers commonly shift the steady-state inactivation of these channels, we observed very small or no impact on the two channels by paroxetine and fluoxetine (Theriault et al, 2014;Scholz, 2002).…”

“…Silicone-free tubing was used since Poulin et al had observed that fluoxetine adheres to silicone, which may considerably change the applied concentrations (Poulin et al, 2014). Fresh drugs working solutions were prepared daily from the stock solution.…”

Carcinoid heart disease involving the left heart: a case report and biomarker analysis

“…1 Without treatment, carcinoid heart disease has a poor prognosis with a 3 year survival rate as low as 31% (compared with 68% in patients without concomitant heart disease). 4 NETs of the small bowel, followed by the lung, large bowel, pancreas, appendix, and ovaries, have the highest incidence of heart disease. 4 NETs of the small bowel, followed by the lung, large bowel, pancreas, appendix, and ovaries, have the highest incidence of heart disease.…”

“…4 NETs of the small bowel, followed by the lung, large bowel, pancreas, appendix, and ovaries, have the highest incidence of heart disease. 4 Cardiac involvement can vary widely in patients. 4 Cardiac involvement can vary widely in patients.…”