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Vol. 284, Issue 1, 269-277, 1998
Department of Pharmacology, College of Medicine, University of
California, Irvine, Irvine, California
The contractile roles of the M2 and M3
muscarinic receptors were investigated in guinea pig longitudinal
colonic smooth muscle. Prior treatment of the colon with
N-(2-chloroethyl)-4-piperidinyl diphenylacetate (4-DAMP mustard) (40 nM) in combination with
[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3b][1,4]benzodiazepine-6-one (AF-DX 116) (1.0 µM) caused a subsequent, irreversible
inhibition of oxotremorine-M-induced contractions when measured after
extensive washing. The estimate of the degree of receptor inactivation
after 2 hr (97%) was not much greater than that measured after 1 hr (95%), which suggests that both 4-DAMP mustard-sensitive and
-insensitive muscarinic subtypes contribute to the contractile
response. Pertussis toxin treatment had no significant inhibitory
effect on the control contractile response to oxotremorine-M, but
caused an 8.8-fold increase in the EC50 value measured
after a 2-hr treatment with 4-DAMP mustard. These results suggest that,
after elimination of most of the M3 receptors with 4-DAMP
mustard, the contractile response can be mediated by the pertussis
toxin-sensitive M2 receptor. After pertussis toxin
treatment, the kinetics of alkylation of muscarinic receptors in the
colon were consistent with a single, 4-DAMP mustard-sensitive,
M3 receptor subtype mediating the contractile response.
When measured after a 2-hr treatment with 4-DAMP mustard and in the
presence of histamine (0.30 µM) and either forskolin (10 µM) or
isoproterenol (0.60 µM), the contractile responses to oxotremorine-M
were pertussis toxin-sensitive and potently antagonized by the
M2 selective antagonist, AF-DX 116. Collectively, our
results indicate that the M2 receptor elicits contraction through two mechanisms, a direct contraction and an indirect
contraction by preventing the relaxant effects of cAMP-generating
agents.
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