M2 muscarinic receptors inhibit isoproterenol-induced relaxation of canine airway smooth muscle

L. B. Fernandes, Allison Fryer, C. A. Hirshman

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Classification of muscarinic receptors in the central airways has revealed the coexistence of M2 and M3 muscarinic receptors in this tissue, with the M2 subtype being predominant. Although M3 muscarinic receptors have been linked to airway smooth muscle contraction, a functional role for the M2 subtype in this tissue has been unclear. In nonairway smooth muscle, stimulation of the M2 muscarinic receptor has been shown to be associated with inhibition of adenylyl cyclase. In the present study, characterization of muscarinic receptors in canine tracheal smooth muscle confirmed that the majority of these muscarinic receptors were of the M2 subtype (89 ± 3%), with a minor population of M3 receptors (11 ± 3%). In functional studies, both isoproterenol and forskolin cause a dose-dependent relaxation of precontracted airway smooth muscle. In tissues precontracted with methacholine, 11-{[[2-(diethylamino)methyl]-1-piperidinyl]acetyl}5,11- dihydro-6H-pyrido[2,3-6][1,4]benzodiazepine-6-one (AF-DX 116), a selective M2 antagonist, shifted dose-response curves to both isoproterenol and forskolin significantly to the left. In contrast, AF-DX 116 did not alter relaxation induced by the K+ channel opener BRL 38227. Furthermore, the ability of AF-DX 116 to enhance isoproterenol-induced relaxation appears to be limited to smooth muscle precontracted with muscarinic agonists because AF-DX 116 had no effect on isoproterenol dose-response curves in muscle strips precontracted with histamine. Hexahydrosiladifenidol (HHSiD), a selective antagonist for M3 receptors, did not shift the isoproterenol dose- response curve in muscle precontracted with methacholine. This study demonstrates that stimulation of M2 muscarinic receptors in canine airway smooth muscle plays an important role in functional antagonism by reducing the relaxation caused by agents such as isoproterenol and forskolin.

Original languageEnglish (US)
Pages (from-to)119-126
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume262
Issue number1
StatePublished - 1992
Externally publishedYes

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Muscarinic M2 Receptors
Isoproterenol
Smooth Muscle
Canidae
Colforsin
Muscarinic M3 Receptors
Methacholine Chloride
Muscarinic Receptors
Cromakalim
Muscarinic Agonists
Muscles
Muscle Contraction
Adenylyl Cyclases
Histamine
otenzepad
Population

ASJC Scopus subject areas

  • Pharmacology

Cite this

M2 muscarinic receptors inhibit isoproterenol-induced relaxation of canine airway smooth muscle. / Fernandes, L. B.; Fryer, Allison; Hirshman, C. A.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 262, No. 1, 1992, p. 119-126.

Research output: Contribution to journalArticle

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abstract = "Classification of muscarinic receptors in the central airways has revealed the coexistence of M2 and M3 muscarinic receptors in this tissue, with the M2 subtype being predominant. Although M3 muscarinic receptors have been linked to airway smooth muscle contraction, a functional role for the M2 subtype in this tissue has been unclear. In nonairway smooth muscle, stimulation of the M2 muscarinic receptor has been shown to be associated with inhibition of adenylyl cyclase. In the present study, characterization of muscarinic receptors in canine tracheal smooth muscle confirmed that the majority of these muscarinic receptors were of the M2 subtype (89 ± 3{\%}), with a minor population of M3 receptors (11 ± 3{\%}). In functional studies, both isoproterenol and forskolin cause a dose-dependent relaxation of precontracted airway smooth muscle. In tissues precontracted with methacholine, 11-{[[2-(diethylamino)methyl]-1-piperidinyl]acetyl}5,11- dihydro-6H-pyrido[2,3-6][1,4]benzodiazepine-6-one (AF-DX 116), a selective M2 antagonist, shifted dose-response curves to both isoproterenol and forskolin significantly to the left. In contrast, AF-DX 116 did not alter relaxation induced by the K+ channel opener BRL 38227. Furthermore, the ability of AF-DX 116 to enhance isoproterenol-induced relaxation appears to be limited to smooth muscle precontracted with muscarinic agonists because AF-DX 116 had no effect on isoproterenol dose-response curves in muscle strips precontracted with histamine. Hexahydrosiladifenidol (HHSiD), a selective antagonist for M3 receptors, did not shift the isoproterenol dose- response curve in muscle precontracted with methacholine. This study demonstrates that stimulation of M2 muscarinic receptors in canine airway smooth muscle plays an important role in functional antagonism by reducing the relaxation caused by agents such as isoproterenol and forskolin.",
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