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

Previous studies demonstrated that chlorzoxazone or 1-ethyl-2-benzimidazoli none (1-EBIO) enhances transepithelial Cl- secretion by increasing basolate ral K+ conductance (G(K)) (Singh AK, Devor DC, Gerlach AC, Gondor M, Pilews ki JM, and Bridges RJ. J Pharmacol Exp Ther 292: 778-787, 2000). Hence thes e 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 regul ator 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 muM) or 1-EBIO (2 mM) increased the amiloride-sensitive I-sc similar to2.5 -fold. This overlapping specificity may preclude use of these compounds as CF therapeutics. Assaying for changes in the basolateral G(K) with a K+ gra dient plus the pore-forming antibiotic amphotericin B revealed that chlorzo xazone or 1-EBIO evoked an similar to 10-fold increase in clotrimazole-sens itive G(K). In contrast, chlorzoxazone did not alter epithelial Na+ channel -mediated currents across basolateral-permeabilized monolayers or in Xenopu s oocytes. These data further suggest that alterations in basolateral G(K) alone can modulate epithelial Na+ transport.