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Am J Physiol Lung Cell Mol Physiol 283: L1125-L1132, 2002. First published June 21, 2002; doi:10.1152/ajplung.00084.2002
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Vol. 283, Issue 5, L1125-L1132, November 2002

Muscarinic M2 receptors in acetylcholine-isoproterenol functional antagonism in human isolated bronchus

Benjamin Sarria1, Emmanuel Naline2, Yong Zhang3, Julio Cortijo1, Mathieu Molimard2, Joelle Moreau2, Patrice Therond2, Charles Advenier2, and Esteban J. Morcillo1

1 Departament de Farmacologia, Facultat de Medicina i Odontologia, Universitat de València, 46010 València, Spain; 2 Faculté de Médecine Paris-Ouest, Unité de Formation et de Recherche Biomédicale des Saint Pères, and Centre Hospitalier de Versailles, 78157 Le Chesnay, France; and 3 Shanghai Second Medical University, 200025 Shanghai, China

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 Emax inhibition for 100 µM ACh = 30%) more than the same levels of histamine contraction. The M2 receptor-selective antagonist methoctramine (1 µM) 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 pKB (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.

airway smooth muscle; muscarinic receptors; methoctramine; 4-diphenylacetoxy-N-(2-chloroethyl)piperadine hydrochloric acid


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