Block by fluoxetine of volume‐regulated anion channels

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Abstract
We have used the whole‐cell patch clamp technique to study the effect of fluoxetine, a commonly used antidepressant drug, on the volume‐regulated anion channel (VRAC) in calf pulmonary artery endothelial (CPAE) cells. We also examined its effects on other Cl− channels, i.e. the Ca2+‐activated Cl− current (ICl,Ca) and the cystic fibrosis transmembrane conductance regulator (CFTR) to assess the specificity of this compound for VRAC. At pH 7.4 fluoxetine induced a fast and reversible block of the volume‐sensitive chloride current (ICl,swell), with a Ki value of 6.0±0.5 μM (n=6‐9). The blocking efficiency increased with increasing extracellular pH (Ki=0.32±0.01 μM at pH 8.8, n=3‐9), indicating that the blockade is mediated by the uncharged form of fluoxetine. Fluoxetine inhibited Ca2+‐activated Cl− currents, ICl,Ca, activated by loading CPAE cells via the patch pipette with 1000 nM free Ca2+ (Ki=10.7±1.6 μM at pH 7.4, n=3‐5). The CFTR channel, transiently transfected in CPAE cells, was also inhibited with a Ki value of 26.9±9.4 μM at pH 7.4 (n=3). This study describes for the first time the effects of fluoxetine on anion channels. Our data reveal a potent block of VRAC at fluoxetine concentrations close to plasma concentrations. The results suggest a hydrophobic interaction with high affinity between uncharged fluoxetine and volume‐activated chloride channels. Ca2+‐activated Cl− currents and CFTR are also blocked by fluoxetine, revealing a novel characteristic of the drug as a chloride channel modulator. British Journal of Pharmacology (1999) 126, 508–514; doi:10.1038/sj.bjp.0702314

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