Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 291; no. 2; pp. R454 - R463
• Main Authors: Canning, Brendan J, Farmer, David G, Mori, Nanako
• Format: Journal Article
• Language: English
• Published: United States 01.08.2006
• Subjects: Anesthesia; Animals; Autacoids - physiology; Citric Acid - pharmacology; Cough - chemically induced; Dose-Response Relationship, Drug; Epithelium - physiology; Evoked Potentials; Guinea Pigs; Male; Muscle, Smooth - physiology; Neurons, Afferent - drug effects; Neurons, Afferent - physiology; Time Factors; Trachea - innervation; Trachea - physiology
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00862.2005

The Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland Submitted 8 December 2005 ; accepted in final form 13 February 2006 Experiments carried out in conscious guinea pigs suggest that citric acid-evoked coughing is partly mediated by transient receptor potential vanilloid type 1 (TRPV1) receptor-dependent activation of tachykinin-containing, capsaicin-sensitive C fibers. In vitro electrophysiological analyses indicate, however, that acid also activates capsaicin-sensitive and -insensitive vagal afferent nerves by a TRPV1-independent mechanism, and studies in anesthetized guinea pigs show that coughing evoked by acid is mediated by activation of capsaicin-insensitive vagal afferent nerves. In the present study, we have characterized the mechanisms of citric acid-evoked coughing in anesthetized guinea pigs. Drugs were administered directly to the Krebs buffer perfusing the extrathoracic trachea. Citric acid was applied topically to the tracheal mucosa, directly into the tracheal perfusate in increasing concentrations and at 1-min intervals. Citric acid dose dependently evoked coughing in anesthetized guinea pigs. This was mimicked by hydrochloric acid but not by sodium citrate. The coughing evoked by acid was nearly or completely abolished by TTX or by cutting the recurrent laryngeal nerves. Perfusing the trachea with a low Cl – buffer potentiated the acid-induced cough reflex. In contrast, prior capsaicin desensitization, 10 µM capsazepine, Ca 2+ -free perfusate, 0.1 µM iberiotoxin, 1 µM atropine, 10 µM isoproterenol, 10 µM albuterol, 3 µM indomethacin, 0.1 µM HOE-140, a combination of neurokinin 1 (NK 1 ; CP-99994), NK 2 (SR-48968), and NK 3 (SB-223412) receptor antagonists (0.1 µM each), a combination of histamine H 1 (3 µM pyrilamine) and cysLT 1 (1 µM ICI-198615) receptor antagonists, superior laryngeal nerve transection, or epithelium removal did not inhibit citric acid-evoked coughing. These and other data indicate that citric acid-evoked coughing in anesthetized guinea pigs is mediated by direct activation of capsaicin-insensitive vagal afferent nerves, perhaps through sequential activation of acid-sensing ion channels and chloride channels. TRPV1; capsaicin; rapidly adapting receptor Address for reprint requests and other correspondence: B. J. Canning, The Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 (e-mail: bjc{at}jhmi.edu )