Background and Aims: Fluoxetine is a commonly prescribed antidepressant with frequent gastrointestinal side effects. The aim of this study was to examine the effects of fluoxetine on isolated canine and human jejunal circular smooth muscle cells. Methods: Patch clamp and dual wavelength ratio techniques were used. Results: In amphotericin-perforated patch whole-cell recordings, fluoxetine at 100 nmol/L, 1 μmol/L, and 10 μmol/L concentrations decreased the outwardly delayed rectifier potassium current in canine cells by 12% ± 3%, 27% ± 12%, and 37% ± 3%, respectively, and depolarized the membrane potential by 9.7 ± 1.8 mV at 10 μmol/L. At 100 μmol/L and 1 mmol/L concentrations, fluoxetine increased the outward current by 88% ± 40% and 475% ± 270%, respectively. The increase in the outward current was blocked by charybdotoxin, suggesting an effect on the calcium- activated potassium current. In human cells, fluoxetine at 1 μmol/L decreased the outward potassium current by 26% ± 4% and at 100 μmol/L increased the outward potassium current by 134% ± 22%. Conclusions: Fluoxetine had direct effects on canine and human jejunal circular smooth muscle cells. Low concentrations decreased the outwardly delayed rectifier potassium current, and higher concentrations activated calcium-activated potassium channels. The results may in part explain the frequent gastrointestinal side effects of the drug.
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