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Title
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Selective muscarinic receptor antagonists inhibit smooth muscle contraction in rabbit trachea without increasing the release of acetylcholine
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Author
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Abstract
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| Although five muscarinic receptor subtypes have now been cloned, only three receptor subtypes have been demonstrated pharmacologically in bronchial tissue (designated M1, M2 and M3). By using drugs that show selectivity for these receptor subtypes, in combination with a sensitive and specific high-pressure liquid chromatography method that enables the direct measurement of acetylcholine (ACh) release, the existence and function of these muscarinic receptor subtypes was investigated in rabbit trachea in vitro. Atropine and ipratropium bromide, nonselective antimuscarinic agents, dose-dependently suppressed contraction of rabbit trachea induced by transmural electrical stimulation, but at the same time enhanced the release of ACh, suggesting the presence of an autoregulatory feed-back system. The M2/M4 receptor antagonists methoctramine, 11-({2-[(diethylamino)methyl]-1 -piperidinyl}acetyl)-5,11-dihydro-6H-prido(2,3-b) (1,4)benzodiazepine-6-one, 5,11-dihydro-11-{[(2-{2-[(dipropylamino) methyl]-1-piperidinyl}ethyl)amino]carbonyl}-6H-pyrido (,3-b)(1,4)benzodiazepine-6-one and 11-({4-[4-diethylamino) butyl]-1-piperidinyl}acetyl)-5,11-dihydro-6H-pyrido(2,3-b) (1,4)benzodiazepine-6-one also dose-dependently increased ACh release during electrical stimulation, indicating that the powerful negative feedback system is mediated by presynaptic autoreceptors of the M2 or M4 type. This was further supported by the finding that the M2 receptor agonist arecaidine propargyl ester not only inhibited ACh release during electrical stimulation, but also prevented the increased output of ACh induced by 11-({2-[(diethylamino)methyl]-l -piperidinyl}acetyl)-5, 11-dihydro-6H-pyrido(2,3-b)(1, 4)benzodiazepine-6-one Hexahydro-sila-difenidol and its p-fluoro analog, muscarinic receptor antagonists with a high selectivity for the M3 over M2 subtype, inhibited tracheal smooth muscle contraction, but had no stimulatory effect on ACh release, which seems therefore to be modulated by M2 receptors. These data suggest that muscarinic receptor antagonists with a high selectivity for the M3 receptor subtype may provide a more safe and effective antimuscarinic therapy for the treatment of obstructive airway disease in the future. |
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Language
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English
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Source (journal)
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The journal of pharmacology and experimental therapeutics. - Baltimore, Md
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Publication
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Baltimore, Md
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1992
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ISSN
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0022-3565
[print]
1521-0103
[online]
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Volume/pages
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263
:2
(1992)
, p. 773-779
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ISI
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A1992JX70400050
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Full text (publisher's version - intranet only)
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