title: Muscarinic M2 receptors in acetylcholine-isoproterenol functional antagonism in human isolated bronchus.
abstract: The muscarinic functional antagonism of isoproterenol relaxation and the contribution of muscarinic M2 receptors were examined in human isolated bronchus. In intact tissues, acetylcholine (ACh) precontraction decreased isoproterenol potency and maximal relaxation (-log EC50 shift = -1.49 +/- 0.16 and E(max) inhibition for 100 microM ACh = 30%) more than the same levels of histamine contraction. The M2 receptor-selective antagonist methoctramine (1 microM) reduced this antagonism in ACh- but not histamine-contracted tissues. Similar results were obtained for forskolin-induced relaxation. After selective inactivation of M3 receptors with 4-diphenylacetoxy-N-(2-chloroethyl)piperadine hydrochloric acid (30 nM), demonstrated by abolition of contractile and inositol phosphate responses to ACh, muscarinic recontractile responses were obtained in U-46619-precontracted tissues fully relaxed with isoproterenol. Methoctramine antagonized recontraction, with pK(B) (6.9) higher than in intact tissues (5.4), suggesting participation of M2 receptors. In M3-inactivated tissues, methoctramine augmented the isoproterenol relaxant potency in U-46619-contracted bronchus and reversed the ACh-induced inhibition of isoproterenol cAMP accumulation. These results indicate that M2 receptors cause indirect contraction of human bronchus by reversing sympathetically mediated relaxation and contribute to cholinergic functional antagonism.
authors.affiliation: Departament de Farmacologia, Facultat de Medicina i Odontologia, Universitat de València, 46010 València, Spain.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Sarria
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Naline
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Julio
authors.initials: J
authors.lastname: Cortijo
authors.forename: Mathieu
authors.initials: M
authors.lastname: Molimard
authors.forename: Joelle
authors.initials: J
authors.lastname: Moreau
authors.forename: Patrice
authors.initials: P
authors.lastname: Therond
authors.forename: Charles
authors.initials: C
authors.lastname: Advenier
authors.forename: Esteban J
authors.initials: EJ
authors.lastname: Morcillo
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000601:surgery; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*
chemical_list: D018727:Muscarinic Antagonists; D010880:Piperidines; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D005576:Colforsin; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D000242:Cyclic AMP; D007545:Isoproterenol; D000109:Acetylcholine