Chloride channel function is linked to epithelium-dependent airway relaxation. Fortner, Christopher N., John N. Lorenz, and Richard J. Paul. University of Cincinnati College of Medicine, Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267
APStracts 7:0258L, 2000.
We previously reported that substance P (SP) and ATP evoke transient, epithelium- dependent relaxation of mouse tracheal smooth muscle. Since both SP and ATP are known to evoke transepithelial Cl«minus» secretion across epithelial monolayers, we tested the hypothesis that epithelium-dependent relaxation of mouse trachea depends on Cl«minus» channel function. In perfused mouse tracheas, the responses to SP and ATP were both inhibited by the Cl«minus» channel inhibitors diphenylamine-2-carboxylate and 5-nitro-2-(3-phenylpropylamino)benzoate. Relaxation to ATP or SP was unaffected by 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS) and relaxation to SP by either DIDS or DNDS. Replacing Cl«minus» in the buffer solutions with the impermeable anion gluconate on both sides of the trachea inhibited relaxation to SP or ATP. In contrast, increasing the gradient for Cl«minus» secretion using Cl«minus»-free media only in the tracheal lumen enhanced the relaxation to SP or ATP. We conclude that Cl«minus» channel function is linked to receptor-mediated, epithelium-dependent relaxation. The finding that relaxation to SP was not blocked by DIDS suggested the involvement of a DIDS-insensitive Cl«minus» channel, potentially the cystic fibrosis transmembrane conductance regulator (CFTR) Cl«minus» channel. To test this hypothesis we evaluated tracheas from CFTR-deficient mice (CFTR«minus»/«minus») and found that the peak relaxation to SP or ATP was not significantly different from those responses in wild-type littermates. This suggests that a DIDS-insensitive Cl«minus» channel other than CFTR is active in the SP response. This work introduces a possible role for Cl«minus» pathways in the modulation of airway smooth muscle function and may have implications for fundamental studies of airway function as well as therapeutic approaches to pulmonary disease. 

Received 11 February 2000; accepted in final form 7 September 2000
APS Manuscript Number L4-0.
Article publication pending Am J Physiol Lung Cell Mol Physiol
ISSN 1080-4757 Copyright 2000 The American Physiological Society.
Published in APStracts on 30 November 2000