title: Downregulation of the cough reflex by aclidinium and tiotropium in awake and anesthetized rabbits.
abstract: Long-acting muscarinic receptor antagonists (LAMAs) have been reported to attenuate cough in preclinical and clinical studies. The present study was performed on rabbits to compare aclidinium and tiotropium efficacy in the downregulation of the cough reflex. This reflex was evoked by citric acid inhalation in unanesthetized animals and by both citric acid inhalation and mechanical stimulation of the tracheobronchial tree in anesthetized animals 90 min following the inhalation of each drug (nebulizer output always at 1 mL/min). Aclidinium 4 mg/mL and tiotropium 200 μg/mL inhaled in 1 min proved to have similar protective effect on methacholine-induced bronchoconstriction in anesthetized animals. The total dosage employed for aclidinium and tiotropium was 4 mg and 200 μg, respectively. In awake animals, similar reductions in the cough number were observed following 10-min inhalation of each drug with a slight, not significant tendency to higher antitussive effects for aclidinium. In anesthetized animals, 1-min inhalation of each drug caused similar depressant effects on cough responses induced by both mechanical and chemical stimulation. A complete suppression of cough responses to mechanical stimuli was seen in some preparations. The results strongly suggest that the LAMA-induced downregulation of cough may be mediated not only by transient receptor potential vanilloid type 1 channels, as already reported, but also by acid-sensing ion channels and mechanoreceptors. The route of administration along with the more rapid hydrolysis of aclidinium into inactive metabolites minimize potential systemic side effects and give to this drug a very favorable safety profile.
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, Sezione Scienze Fisiologiche, Università degli Studi di Firenze, Viale G.B. Morgagni 63, 50134 Firenze, Italy. Electronic address: donatella.mutolo@unifi.it.
authors.forename: Donatella
authors.initials: D
authors.lastname: Mutolo
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, Sezione Scienze Fisiologiche, Università degli Studi di Firenze, Viale G.B. Morgagni 63, 50134 Firenze, Italy.
authors.forename: Elenia
authors.initials: E
authors.lastname: Cinelli
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, Sezione Scienze Fisiologiche, Università degli Studi di Firenze, Viale G.B. Morgagni 63, 50134 Firenze, Italy.
authors.forename: Ludovica
authors.initials: L
authors.lastname: Iovino
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, Sezione Scienze Fisiologiche, Università degli Studi di Firenze, Viale G.B. Morgagni 63, 50134 Firenze, Italy.
authors.forename: Tito
authors.initials: T
authors.lastname: Pantaleo
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, Sezione Scienze Fisiologiche, Università degli Studi di Firenze, Viale G.B. Morgagni 63, 50134 Firenze, Italy.
authors.forename: Fulvia
authors.initials: F
authors.lastname: Bongianni
mesh_terms: D000280:Administration, Inhalation; D000758:Anesthesia / Q000379:methods; D000818:Animals; D000996:Antitussive Agents / Q000008:administration & dosage / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology; D003371:Cough / Q000188:drug therapy*; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D000069447:Tiotropium Bromide / Q000008:administration & dosage / Q000494:pharmacology*; D014326:Tropanes / Q000008:administration & dosage / Q000494:pharmacology*; D014851:Wakefulness
chemical_list: D000996:Antitussive Agents; D001993:Bronchodilator Agents; D003692:Delayed-Action Preparations; D018727:Muscarinic Antagonists; D014326:Tropanes; D016210:Methacholine Chloride; C542859:aclidinium bromide; D000069447:Tiotropium Bromide
keywords: ASICs; Aclidinium; Airway mechanoreceptors; Long-acting muscarinic receptor antagonists; The cough reflex; Tiotropium