Block of volume-regulated anion channels by selective serotonin reuptake inhibitors.
We have used the whole-cell patch clamp technique to study the effects of the commonly used antidepressants sertraline, paroxetine, citalopram and fluvoxamine on the volume-regulated anion channel (VRAC) in endothelial cells. It was the purpose of the present experiments to investigate whether VRAC block is a general property of this group of selective serotonin reuptake inhibitors (SSRIs). At pH 7.4, all SSRIs induced a fast and reversible block of the volume-sensitive chloride current ( I(Cl,swell)), with an IC(50) value of 2.1+/-0.5 microM for sertraline, 2.7+/-0.2 microM for paroxetine, 12.3+/-1.4 microM for fluvoxamine and 27.7+/-2.8 microM for citalopram. The block was enhanced at more alkaline pH, indicating that it is mediated by the uncharged form. This study describes the effects of a variety of SSRIs on an anion channel. Our data reveal a potent block and suggest a hydrophobic interaction of high affinity between the uncharged SSRI and volume-regulated anion channels. We conclude that VRAC block is a general property of this pharmacological class of selective serotonin reuptake inhibitors.
KU Leuven, Laboratorium voor Fysiologie, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
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Maertens
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Droogmans
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Verbesselt
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Nilius
D000928:Antidepressive Agents / Q000494:pharmacology; D002478:Cells, Cultured; D018118:Chloride Channels / Q000037:antagonists & inhibitors*; D015283:Citalopram / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D016666:Fluvoxamine / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007038:Hypotonic Solutions / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008564:Membrane Potentials / Q000187:drug effects; D017374:Paroxetine / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011651:Pulmonary Artery / Q000166:cytology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline / Q000737:chemistry / Q000494:pharmacology
D000928:Antidepressive Agents; D018118:Chloride Channels; D015283:Citalopram; D016666:Fluvoxamine; D007038:Hypotonic Solutions; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline