Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 283, Issue 5, Pages L1125-L1132Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00084.2002
Keywords
airway smooth muscle; muscarinic receptors; methoctramine; 4-diphenylacetoxy-N-(2-chloroethyl) piperadine hydrochloric acid
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The muscarinic functional antagonism of isoproterenol relaxation and the contribution of muscarinic M-2 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 muM ACh = 30%) more than the same levels of histamine contraction. The M-2 receptor-selective antagonist methoctramine (1 muM) reduced this antagonism in ACh- but not histamine-contracted tissues. Similar results were obtained for forskolin-induced relaxation. After selective inactivation of M-3 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 M-2 receptors. In M-3-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 M-2 receptors cause indirect contraction of human bronchus by reversing sympathetically mediated relaxation and contribute to cholinergic functional antagonism.
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