Differential effects of fluoxetine enantiomers in mammalian neural and cardiac tissues

Magyar, János; Rusznák, Zoltán; Harasztosi, Csaba; Körtvély, Ágnes; Pacher, Pál; Bányász, Tamás; Pankucsi, Csaba; Kovács, László; Szücs, G; Nánási, Péter P.; Kecskeméti, Valéria

doi:10.3892/ijmm.11.4.535

Cited by 24 publications

(21 citation statements)

References 38 publications

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“…15,[30][31][32] These contradictory effects may be explained by species differences in electrophysiological properties. For example, action potential prolongation by inhibition of I Kr is clearly species-dependent, as shown in simulations and experimental studies.…”

Section: Discussionmentioning

confidence: 99%

Slow Delayed Rectifier Potassium Current Blockade Contributes Importantly to Drug-Induced Long QT Syndrome

Veerman

Verkerk

Blom

et al. 2013

Circ: Arrhythmia and Electrophysiology

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Background-Drug-induced long QT syndrome is generally ascribed to inhibition of the cardiac rapid delayed rectifier potassium current (I Kr ). Effects on the slow delayed rectifier potassium current (I Ks ) are less recognized. Triggered by a patient who carried the K422T mutation in KCNQ1 (encoding the α-subunit of the I Ks channel), who presented with excessive QT prolongation and high serum levels of norfluoxetine, we investigated the effects of fluoxetine and its metabolite norfluoxetine on I Ks . Methods and Results-ECG data from mutation carriers and noncarriers revealed that the K422T mutation per se had mild clinical effects. Patch clamp studies, performed on HEK293 cells, showed that heterozygously expressed K422T KCNQ1/ KCNE1 channels had a positive shift in voltage dependence of activation and an increase in deactivation rate. Fluoxetine and its metabolite norfluoxetine both inhibited KCNQ1/KCNE1 current, with norfluoxetine being the most potent. Moreover, norfluoxetine increased activation and deactivation rates. Computer simulations of the effects of norfluoxetine on I Ks and I Kr demonstrated significant action potential prolongation, to which I Ks block contributed importantly. Although the effects of the mutation per se were small, additional I Ks blockade by norfluoxetine resulted in more prominent QTc prolongation in mutation carriers than in noncarriers, demonstrating synergistic effects of innate and drug-induced I Ks blockade on QTc prolongation. Conclusions-I

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Section: Discussionmentioning

confidence: 99%

Slow Delayed Rectifier Potassium Current Blockade Contributes Importantly to Drug-Induced Long QT Syndrome

Veerman

Verkerk

Blom

et al. 2013

Circ: Arrhythmia and Electrophysiology

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“…The major cause of the higher mortality rate in psychiatric patients versus the general population is sudden cardiac death, which mainly results from arrhythmias that occur during treatments with psychotropic drugs. It has been reported that fluoxetine decreases the maximum rate of rise of the depolarization phase (V max ) of ventricular cell preparations Magyar et al, 2003), but little is known about the direct effect of fluoxetine on the biophysical properties of Na v 1.5.…”

Section: Introductionmentioning

confidence: 99%

Fluoxetine Blocks Na_v1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics

et al. 2014

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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.

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“…In some cases, the pure isomer was even shown to provide an advantage in the clinical use of a compound administered in the form of racemate so far (e.g. Valenzuela et al 1995;Stoschitzky et al 2001;Magyar et al 2003;Eap et al 2007;Wang et al 2008). Thus, it might be beneficial to produce and test the pure S-isomer of 444 if this compound was considered to be used in the clinical practise in the future.…”

Section: Discussionmentioning

confidence: 99%

Effect of Newly Synthesized Compounds 44Bu and 444 on QRS-Complex Width and Fast Sodium Current: Differences between Isomers

Kilianová

Bébarová

Beránková³

et al. 2010

Acta Vet. Brno

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Two newly synthesized short-acting agents 44Bu and 444 were observed to suppress the aconitine-induced arrhythmias and block the fast sodium current I Na in the rat heart. No data about their effect on the electrocardiographic parameters are available. In this study, we explored the effect of both racemates and particular isomers of 44Bu and 444 on the QRS-complex width in vivo in rats and on I Na in isolated rat ventricular myocytes. All variants of 44Bu and 444 (1.5 mg/kg) caused a significant QRS-widening reaching the peak effect at the 1 st or 2 nd min after their intravenous administration. 44Bu racemate widened the QRS-complex from 16.8 ± 0.4 to 26.3 ± 0.5 ms (by 57%), significantly more than R-(33%-widening) and S-isomer (36%-widening). 444 racemate widened the QRS-complex from 20.8 ± 1.0 to 34.1 ± 0.9 ms (by 64%), which was comparable to S-isomer (63%-widening), however, substantially more than R-isomer (40%-widening). Regarding the effect on I Na , 44Bu caused a significantly deeper I Nablock compared to 444 when applied at the same concentration of 3 µmol/l (0.1 mg/kg). 44Bu racemate and R-isomer blocked I Na similarly (91.7 ± 0.8 and 91.8 ± 1.6%-block, respectively) and significantly more than S-isomer (82.4 ± 2.3%-block). 444 R-isomer blocked I Na less than racemate and S-isomer (by 31.7 ± 3.9% vs. 48.3 ± 4.7 and 50.2 ± 4.1%, respectively). We conclude that both racemates and particular isomers of 44Bu and 444 induce a QRS-widening and block I Na in the rat heart, however, their effects notably differed. The relative widening of the QRS-complex after application of 44Bu did not conform to the level of I Na -block observed in isolated cardiomyocytes which stresses the importance of in vivo experiments in the pre-clinical testing of new drugs.

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Differential effects of fluoxetine enantiomers in mammalian neural and cardiac tissues

Cited by 24 publications

References 38 publications

Slow Delayed Rectifier Potassium Current Blockade Contributes Importantly to Drug-Induced Long QT Syndrome

Slow Delayed Rectifier Potassium Current Blockade Contributes Importantly to Drug-Induced Long QT Syndrome

Fluoxetine Blocks Na_v1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics

Effect of Newly Synthesized Compounds 44Bu and 444 on QRS-Complex Width and Fast Sodium Current: Differences between Isomers

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Differential effects of fluoxetine enantiomers in mammalian neural and cardiac tissues

Cited by 24 publications

References 38 publications

Slow Delayed Rectifier Potassium Current Blockade Contributes Importantly to Drug-Induced Long QT Syndrome

Slow Delayed Rectifier Potassium Current Blockade Contributes Importantly to Drug-Induced Long QT Syndrome

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

Effect of Newly Synthesized Compounds 44Bu and 444 on QRS-Complex Width and Fast Sodium Current: Differences between Isomers

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Fluoxetine Blocks Na_v1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics