Activation of chloride secretion in cystic fibrosis cells and tissues by the substituted imidazole SRI 2931.
Recent interest in nucleotides and related agents as part of clinical trials in cystic fibrosis (CF) therapy have elicited efforts to identify novel compounds capable of activating transepithelial chloride (Cl(-)) transport in CF cells and tissues. From a library of nucleosides, bases, and other substituted heterocycles, 341 compounds were screened for their ability to activate anion transport in CF cells grown on permeable supports. One compound, SRI 2931, was found to confer prolonged and potent activity when administered to the apical surfaces of CF pancreatic epithelial cells, primary CF nasal epithelial cells, non-CF human colonic epithelial cells, and intact tissue taken from mouse models for CF. Concentrations of SRI 2931 (20 microM), which activated Cl(-) transport, had minimal effect on cell proliferation. SRI 2931 was not calcium (Ca(2+)) or cAMP dependent, suggesting important differences from conventional chloride secretagogues. The compound selectively released ATP from the apical, but not basolateral, surfaces of CF cells grown on permeable supports. The magnitude, longevity, and mechanism of action of the response provide a tool for dissecting pathways of epithelial ATP extracellular signaling and Cl(-) permeability.
Jones
Julie R
JR
Vanderbilt University Medical Center, Department of Molecular Physiology and Biophysics, Nashville, Tennessee, USA.
Schwiebert
Erik M
EM
DuVall
Michael D
MD
Venglarik
Charles J
CJ
Wen
Hui
H
Kovacs
Timea
T
Mazur
Marina
M
Clancy
John P
JP
Braunstein
Gavin
G
Bates
Eleanor
E
Greer
Heather
H
Maddry
Joseph A
JA
Sorscher
Eric J
EJ
D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018118:Chloride Channels / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D003106:Colon; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects; D051379:Mice; D018181:Mice, Inbred CFTR; D009298:Nasal Polyps / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D018118:Chloride Channels; D002712:Chlorides; D007093:Imidazoles; C482138:SRI 2931; D000255:Adenosine Triphosphate