Chlorzoxazone or 1-EBIO increases Na(+) absorption across cystic fibrosis airway epithelial cells.

Academic Article

Abstract

  • 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.
  • Keywords

  • Amiloride, Animals, Benzimidazoles, Calcium Channel Agonists, Cell Polarity, Cells, Cultured, Chlorides, Chlorzoxazone, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Diuretics, Dose-Response Relationship, Drug, Epithelial Cells, Epithelial Sodium Channels, Humans, Ion Transport, Muscle Relaxants, Central, Oocytes, Patch-Clamp Techniques, Potassium, Respiratory Mucosa, Sodium, Sodium Channels, Xenopus laevis
  • Digital Object Identifier (doi)

    Author List

  • Gao L; Yankaskas JR; Fuller CM; Sorscher EJ; Matalon S; Forman HJ; Venglarik CJ
  • Start Page

  • L1123
  • End Page

  • L1129
  • Volume

  • 281
  • Issue

  • 5