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Differential effects of fluoxetine enantiomers in mammalian neural and cardiac tissues

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Racemic fluoxetine is a widely used SSRI antidepressant compound having also anticonvulsant effect. In addition, it was shown that it blocked several types of voltage gated ion channels including neural and cardiac calcium channels. In the present study the effects of enantiomers of fluoxetine (R(−)-fluoxetine and S(+)-fluoxetine) were compared on neuronal and cardiac voltage-gated Ca2+ channels using the whole cell configuration of patch clamp techniques, and the anticonvulsant action of these enantiomers was also evaluated in a mouse epilepsy model. In isolated pyramidal neurons of the dorsal cochlear nucleus of the rat the effect of fluoxetine (S(+), R(−) and racemic) was studied on the Ca2+ channels by measuring peak Ba2+ current during ramp depolarizations. All forms of fluoxetine reduced the Ba2+ current of the pyramidal cells in a concentration-dependent manner, with a Kd value of 22.3±3.6 µM for racemic fluoxetine. This value of Kd was higher by one order of magnitude than found in cardiac myocytes with fluoxetine enantiomers (2.4±0.1 and 2.8±0.2 µM). Difference between the effects of the two enantiomers on neuronal Ba2+ current was observed only at 5 µM concentration: R(−)-fluoxetine inhibited 28±3% of the peak current, while S(+)-fluoxetine reduced the current by 18±2% (n=13, P<0.05). In voltage clamped canine ventricular cardiomyocytes both enantiomers of fluoxetine caused a reversible concentration-dependent block of the peak Ca2+ current measured at 0 mV. Significant differences between the two enantiomers in this blocking effect was observed at low concentrations only: S(+)-fluoxetine caused a higher degree of block than R(−)-fluoxetine (56.3±2.2% versus 49.1±2.2% and 95.5±0.9% versus 84.5±3.1% block with 3 and 10 µM S(+) and R(−)-fluoxetine, respectively, P<0.05, n=5). Studied in current clamp mode, micromolar concentrations of fluoxetine shortened action potential duration of isolated ventricular cells, while higher concentrations also suppressed maximum velocity of depolarization and action potential amplitude. This shortening effect was significantly greater in the case of S(+) than R(−)-fluoxetine at 1 and 3 µM concentrations, whereas no differences in their effects on depolarization were observed. In pentylenetetrazole-induced mouse epilepsy model fluoxetine pretreatment significantly increased the 60 min survival rate, survival duration and seizure latency. These effects were more pronounced with the R(−) than the S(+) enantiomer. The results indicate that fluoxetine exerts much stronger suppressive effect on cardiac than neuronal calcium channels. At micromolar concentrations (between 1 and 10 µM) R(−)-fluoxetine is more effective than the S(+) enantiomer on neuronal, while less effective on cardiac calcium channels. The stronger anticonvulsant effect of the R(−) enantiomer may, at least partially, be explained by these differences. Used as an antidepressant or anticonvulsant drug, less severe cardiac side-effects are anticipated with the R(−) enantiomer.
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Document Type: Research Article

Affiliations: Department of Physiology, University of Debrecen, Medical School, H-4012 Debrecen, Hungary

Publication date: January 1, 2003

More about this publication?
  • The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.

    The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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