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- Title
Role of the epithelium and acetylcholine in mediating the contraction to 5-hydroxytryptamine in the mouse isolated trachea.
- Authors
Moffatt, James D.; Cocks, Thomas M.; Page, Clive P.
- Abstract
1. The 5-HT receptor subtype that mediates bronchocontraction and the involvement of neuronal and non-neuronal acetylcholine was assessed in murine isolated tracheae. 2. Atropine (1-10 nM) caused a rightward shift of the methacholine concentration-effect curves (pA(2)=9.0) but reduced the maximum response to 5-HT, suggesting that 5-HT acts as an indirect agonist. The potency of 5-HT receptor agonists (alpha-methyl-5-HT approximately 5-HT>5-carboxamidotryptamine), together with the competitive antagonism of 5-HT by ketanserin (pA(2)=9.4), suggests the involvement of the 5-HT(2A) receptor. 3. While cholinergic twitch responses to electrical field stimulation were abolished by the fast sodium channel inhibitor tetrodotoxin (300 nM), as well as by combined blockade of N-, P- and Q-type voltage-operated calcium channels by omega-conotoxin GVIA (30 nM) and agatoxin IVA (100 nM), responses to 5-HT were unaffected. Similarly, botulinum toxin A (50 nM) inhibited EFS twitch responses, but not contractions to 5-HT. 4. Choline acetyltransferase immunoreactivity was localised to ganglia and nerve fibres as well as approximately half the epithelial cells in the preparation. Removal of the epithelial layer markedly attenuated the contractile response to 5-HT, but had no effect on contractions to either methacholine or EFS. 5. These findings suggest that 5-HT, acting at 5-HT(2A) receptors on mouse tracheal epithelial cells, stimulates these cells to release acetylcholine, which then causes contraction of airway smooth muscle. This phenomenon should be borne in mind in when interpreting studies of murine models of airway disease.
- Subjects
ACETYLCHOLINE; EPITHELIUM; FIBERS; TOXINS; DRUGS; PHYSIOLOGICAL effects of chemicals; CARTILAGE physiology; TRACHEA innervation; CALCIUM antagonists; ANIMAL experimentation; ATROPINE; BORON compounds; BOTULINUM toxin; CALCIUM; CARTILAGE; CELL receptors; COMPARATIVE studies; ELECTRIC stimulation; EPITHELIAL cells; HYDROCARBONS; MARINE toxins; RESEARCH methodology; MEDICAL cooperation; MICE; MUSCLE contraction; PROTEINS; RESEARCH; SEROTONIN; SMOOTH muscle; SURFACE active agents; TRACHEA; EVALUATION research; METHACHOLINE chloride; PHARMACODYNAMICS; PHYSIOLOGY
- Publication
British Journal of Pharmacology, 2004, Vol 141, Issue 7, p1159
- ISSN
0007-1188
- Publication type
journal article
- DOI
10.1038/sj.bjp.0705720