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The M 3 muscarinic receptor links to three different transduction mechanisms with different efficacies in circular muscle of guinea‐pig stomach
Author(s) -
Parekh Anant B.,
Brading Alison F.
Publication year - 1992
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1992.tb14388.x
Subject(s) - pirenzepine , carbachol , muscarinic acetylcholine receptor , endocrinology , chemistry , medicine , contraction (grammar) , muscle contraction , nifedipine , muscarinic acetylcholine receptor m2 , muscarinic acetylcholine receptor m3 , biology , receptor , calcium , biochemistry
1 In a previous publication, we showed that 10 μ m carbachol induced contraction by activating three independent transduction mechanisms in circular smooth muscle of guinea‐pig gastric fundus (Parekh & Brading, 1991). These were: inositol trisphosphate‐mediated intracellular Ca 2+ release, Ca 2+ influx through a nifedipine‐sensitive route and Ca 2+ influx through a receptor operated nifedipine‐insensitive pathway. The former two processes contribute to the phasic contraction and the latter two to the tonic contraction. In this paper, we have studied the effects of muscarinic receptor antagonists with known selectivity for different muscarinic receptor subtypes, on the contraction evoked by 10 μ m carbachol. 2 Low concentrations of pirenzepine (M 1 selective) had little effect on the contraction initiated by carbachol. Higher concentrations (> 1 μ m ) reduced only the phasic component. This concentration of pirenzepine greatly reduced the contraction evoked by 10 μ m carbachol in Ca 2+ ‐free solution, indicating inhibition of intracellular Ca 2+ release. 3 In the presence of 10 μ m nifedipine, the tonic contraction evoked by 10 μ m carbachol (reflecting the receptor‐operated nifedipine‐insensitive route) was abolished by 10 μ m pirenzepine. In the absence of nifedipine pretreatment, however, 10 μ m pirenzepine did not abolish the contraction to 10 μ m carbachol. This contraction was subsequently abolished by nifedipine. 4 Only high concentrations (> 10 μ m ) of the M 2 ‐selective antagonist, gallamine, inhibited the contraction to 10 μ m carbachol. Like pirenzepine, gallamine preferentially inhibited the phasic component of the contraction, indicating an effect on intracellular Ca 2+ release. 5 The non‐selective muscarinic receptor antagonist, atropine, abolished all components of the contraction. At low concentrations, atropine also reduced the phasic component without affecting the tonic one, indicating preferential inhibition of intracellular Ca 2+ release. 6 It is concluded that (i) the different transduction mechanisms have different sensitivities to the antagonists used and (ii) an M 3 receptor activates the three transduction mechanisms with different efficacies.