title: Evidence for prejunctional muscarinic autoreceptors in human and guinea pig trachea.
abstract: Functional studies suggest the presence of prejunctional muscarinic autoreceptors on cholinergic nerves in human airways. However, these studies are an indirect method of evaluating changes in neurally evoked acetylcholine (ACh) release. We have investigated the presence of muscarinic autoreceptors in human and guinea pig trachea by comparing the effects of the muscarinic receptor antagonists pirenzepine (M1), methoctramine (M2), 4-DAMP (M3), and rispenzepine (M1/M3) on cholinergic neural contractile responses evoked by electrical field stimulation (EFS) and [3H]ACh release. The M1, M1/M3, or M3 antagonists inhibited the EFS-evoked cholinergic contractile response in a concentration-dependent manner (4-DAMP > rispenzepine > pirenzepine), whereas methoctramine facilitated this response at low concentrations ( < 3 microM). In ACh release studies, the M3 antagonist had no significant effect, whereas pirenzepine, methoctramine, and rispenzepine significantly increased ACh release in guinea pig trachea. In contrast, ACh release was significantly inhibited by the muscarinic agonist oxotremorine M. Methoctramine and the nonselective antagonist ipratropium bromide, but not the M1, M1/M3, or M3 antagonists, significantly increased ACh release in human trachea. These data suggest the presence of an autoinhibitory receptor on cholinergic nerve terminals in human and guinea pig trachea. In addition, the action of ipratropium bromide at the autoinhibitory receptor may limit its use in the treatment of obstructive airways disease.
authors.affiliation: Department of Thoracic Medicine, National Heart and Lung Institute, London, United Kingdom.
authors.forename: H J
authors.initials: HJ
authors.lastname: Patel
authors.forename: P J
authors.initials: PJ
authors.lastname: Barnes
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: S
authors.initials: S
authors.lastname: Tadjkarimi
authors.forename: M H
authors.initials: MH
authors.lastname: Yacoub
authors.forename: M G
authors.initials: MG
authors.lastname: Belvisi
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000818:Animals; D017660:Autoreceptors / Q000032:analysis* / Q000378:metabolism; D002648:Child; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D009241:Ipratropium / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010095:Oxotremorine / Q000031:analogs & derivatives / Q000494:pharmacology; D010275:Parasympathetic Nervous System / Q000502:physiology; D011976:Receptors, Muscarinic / Q000032:analysis* / Q000378:metabolism; D014132:Trachea / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism
chemical_list: D017660:Autoreceptors; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D010095:Oxotremorine; C042743:oxotremorine M; D009241:Ipratropium; D000109:Acetylcholine