title: Effects of a new cystic fibrosis transmembrane conductance regulator inhibitor on Cl- conductance in human sweat ducts.
abstract: Effective and specific inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel in epithelia has long been needed to better understand the role of anion movements in fluid and electrolyte transport. Until now, available inhibitors have required high concentrations, usually in the millimolar or high micromolar range, to effect even an incomplete block of channel conductance. These inhibitors, including 5-nitro-2(3-phenylpropyl-amino)benzoate (NPPB), bumetamide, glibenclamide and DIDS, are also relatively non-specific. Recently a new anion channel inhibitor, a thiazolidinone derivative, termed CFTRInh-172 has been synthesized and introduced with apparently improved inhibitory properties as shown by effects on anion conductance expressed in cell lines and on secretion in vivo. Here, we assay the effect of this inhibitor on a purely salt absorbing native epithelial tissue, the freshly isolated microperfused human sweat duct, known for its inherently high expression of CFTR. We found that the inhibitor at a maximum dose limited by its aqueous solubility of 5 microm partially blocked CFTR when applied to either surface of the membrane; however, it may be somewhat more effective from the cytosolic side (approximately 70% inhibition). It may also partially inhibit Na+ conductance. The inhibition was relatively slow, with a half time for maximum effect of about 3 min, and showed very slow reversibility. Results also suggest that CFTR Cl- conductance (GCl) was blocked in both apical and basal membranes. The inhibitor appears to exert some effect on Na+ transport as well.
authors.affiliation: Department of Pediatrics, UCSD, 9500 Gilman Drive, La Jolla, CA 92093-0831, USA. pquinton@ucsd.edu
authors.forename: X F
authors.initials: XF
authors.lastname: Wang
authors.forename: M M
authors.initials: MM
authors.lastname: Reddy
authors.forename: P M
authors.initials: PM
authors.lastname: Quinton
mesh_terms: D001565:Benzoates / Q000494:pharmacology*; D002712:Chlorides / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D010766:Phosphorylation; D012965:Sodium Chloride / Q000378:metabolism; D013545:Sweat Glands / Q000187:drug effects / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines
chemical_list: C482900:3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone; D001565:Benzoates; C505032:CFTR protein, human; D002712:Chlorides; D013844:Thiazoles; D053778:Thiazolidines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012965:Sodium Chloride