Ketoconazole activates Cl- conductance and blocks Cl- and fluid absorption by cultured cystic fibrosis (CFPAC-1) cells

Proc Natl Acad Sci U S A. 1993 May 1;90(9):4047-51. doi: 10.1073/pnas.90.9.4047.

Abstract

The role of arachidonic acid metabolites in the regulation of apical cell membrane Cl- conductance and transepithelial transport of fluid and Cl- by cultured pancreatic cells from cystic fibrosis (CFPAC-1) and corrected (PAC-1) cell lines was evaluated by the use of inhibitors. CFPAC-1 cells did not exhibit an apical membrane Cl- conductance, absorbed Cl- and fluid, and did not respond to stimulation or inhibition of cAMP action. PAC-1 cells exhibited a cAMP-responsive apical Cl- conductance, which was blocked by indomethacin, a cyclooxygenase inhibitor. Ketoconazole, an epoxygenase inhibitor, had virtually no effects on PAC-1 cell Cl- conductance but caused CFPAC-1 cells to develop a cAMP-insensitive Cl- conductance, blocked Cl- and fluid absorption, and reduced transepithelial electrical resistance. Ketoconazole treatment effectively reversed the cystic fibrosis defect in these cultured cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorption
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / physiology
  • Chloride Channels
  • Chlorides / metabolism*
  • Colforsin / pharmacology
  • Cyclic AMP / analogs & derivatives
  • Cyclic AMP / metabolism
  • Cyclic AMP / pharmacology
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism*
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Epithelium / drug effects
  • Epithelium / physiology
  • Humans
  • Hydrogen-Ion Concentration
  • Indomethacin / pharmacology
  • Ion Channels / drug effects
  • Ion Channels / physiology*
  • Ketoconazole / pharmacology*
  • Masoprocol / pharmacology
  • Membrane Potentials / drug effects
  • Membrane Proteins / drug effects
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Proadifen / pharmacology
  • Thionucleotides / pharmacology
  • Transfection

Substances

  • CFTR protein, human
  • Chloride Channels
  • Chlorides
  • Ion Channels
  • Membrane Proteins
  • Thionucleotides
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Colforsin
  • adenosine-3',5'-cyclic phosphorothioate
  • Masoprocol
  • Proadifen
  • Cyclic AMP
  • Ketoconazole
  • Indomethacin