Chlorzoxazone or 1-EBIO increases Na(+) absorption across cystic fibrosis airway epithelial cells.
Previous studies demonstrated that chlorzoxazone or 1-ethyl-2-benzimidazolinone (1-EBIO) enhances transepithelial Cl(-) secretion by increasing basolateral K(+) conductance (G(K)) (Singh AK, Devor DC, Gerlach AC, Gondor M, Pilewski JM, and Bridges RJ. J Pharmacol Exp Ther 292: 778-787, 2000). Hence these compounds may be useful to treat cystic fibrosis (CF) airway disease. The goal of the present study was to determine whether chlorzoxazone or 1-EBIO altered ion transport across Delta F508-CF transmembrane conductance regulator homozygous CFT1 airway cells. CFT1 monolayers exhibited a basal short-circuit current that was abolished by apical amiloride (inhibition constant 320 nM) as expected for Na(+) absorption. The addition of chlorzoxazone (400 microM) or 1-EBIO (2 mM) increased the amiloride-sensitive I(sc) approximately 2.5-fold. This overlapping specificity may preclude use of these compounds as CF therapeutics. Assaying for changes in the basolateral G(K) with a K(+) gradient plus the pore-forming antibiotic amphotericin B revealed that chlorzoxazone or 1-EBIO evoked an approximately 10-fold increase in clotrimazole-sensitive G(K). In contrast, chlorzoxazone did not alter epithelial Na(+) channel-mediated currents across basolateral-permeabilized monolayers or in Xenopus oocytes. These data further suggest that alterations in basolateral G(K) alone can modulate epithelial Na(+) transport.
Gao
L
L
Department of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005, USA.
Yankaskas
J R
JR
Fuller
C M
CM
Sorscher
E J
EJ
Matalon
S
S
Forman
H J
HJ
Venglarik
C J
CJ
D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D016764:Cell Polarity; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D002753:Chlorzoxazone / Q000494:pharmacology*; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D004232:Diuretics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D053503:Epithelial Sodium Channels; D006801:Humans; D017136:Ion Transport; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000502:physiology
D001562:Benzimidazoles; C505032:CFTR protein, human; D002120:Calcium Channel Agonists; D002712:Chlorides; D004232:Diuretics; D053503:Epithelial Sodium Channels; D009125:Muscle Relaxants, Central; D015222:Sodium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000584:Amiloride; D012964:Sodium; D002753:Chlorzoxazone; C102635:1-ethyl-2-benzimidazolinone; D011188:Potassium