Block by fluoxetine of volume‐regulated anion channels

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 Ca 2+ ‐activated Cl − current (I Cl,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 (I Cl,swell ), with a K i value of 6.0±0.5 μ M ( n =6‐9). The blocking efficiency increased with increasing extracellular pH ( K i =0.32±0.01 μ M at pH 8.8, n =3‐9), indicating that the blockade is mediated by the uncharged form of fluoxetine. Fluoxetine inhibited Ca 2+ ‐activated Cl − currents, I Cl,Ca , activated by loading CPAE cells via the patch pipette with 1000 n M free Ca 2+ ( K i =10.7±1.6 μ M at pH 7.4, n =3‐5). The CFTR channel, transiently transfected in CPAE cells, was also inhibited with a K i value of 26.9±9.4 μ M 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. Ca 2+ ‐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