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Am J Physiol Lung Cell Mol Physiol 281: L1123-L1129, 2001;
1040-0605/01 $5.00
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Vol. 281, Issue 5, L1123-L1129, November 2001

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

Lin Gao1, James R. Yankaskas2, Catherine M. Fuller3, Eric J. Sorscher3,4, Sadis Matalon3,5,6, Henry Jay Forman1, and Charles J. Venglarik1

Departments of 1 Environmental Health Sciences, 3 Physiology and Biophysics, 4 Medicine, 5 Anesthesiology, and 6 Comparative Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005; and 2 Department of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248

Previous studies demonstrated that chlorzoxazone or 1-ethyl-2-benzimidazolinone (1-EBIO) enhances transepithelial Cl- secretion by increasing basolateral K+ conductance (GK) (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 µM) or 1-EBIO (2 mM) increased the amiloride-sensitive Isc ~2.5-fold. This overlapping specificity may preclude use of these compounds as CF therapeutics. Assaying for changes in the basolateral GK with a K+ gradient plus the pore-forming antibiotic amphotericin B revealed that chlorzoxazone or 1-EBIO evoked an ~10-fold increase in clotrimazole-sensitive GK. 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 GK alone can modulate epithelial Na+ transport.

epithelial sodium channel; cystic fibrosis transmembrane conductance regulator; clotrimazole; amiloride; 1-ethyl-2-benzimidazolinone


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