Chloride channel function is linked to epithelium-dependent airway relaxation.
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- secretion across epithelial monolayers, we tested the hypothesis that epithelium-dependent relaxation of mouse trachea depends on Cl- channel function. In perfused mouse tracheas, the responses to SP and ATP were both inhibited by the Cl- 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 was unaffected by either DIDS or DNDS. Replacing Cl- 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- secretion using Cl- free medium only in the tracheal lumen enhanced the relaxation to SP or ATP. We conclude that Cl- 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- channel, potentially the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. To test this hypothesis, we evaluated tracheas from CFTR-deficient mice 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- channel other than CFTR is active in the SP response. This work introduces a possible role for Cl- 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.
Fortner
C N
CN
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA. chris.fortner@uc.edu
Lorenz
J N
JN
Paul
R J
RJ
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005942:Gluconates / Q000494:pharmacology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018181:Mice, Inbred CFTR; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009579:Nitrobenzoates / Q000494:pharmacology; D010477:Perfusion; D015203:Reproducibility of Results; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000494:pharmacology
D002121:Calcium Channel Blockers; D018118:Chloride Channels; D005942:Gluconates; D009579:Nitrobenzoates; D013267:Stilbenes; D062367:ortho-Aminobenzoates; D013373:Substance P; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid; C022306:4,4'-dinitro-2,2'-stilbenedisulfonic acid; D000255:Adenosine Triphosphate; C001209:fenamic acid; D015232:Dinoprostone; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid