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Journal of Pharmacology and Experimental Therapeutics

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OtherAUTONOMIC PHARMACOLOGY

M4 Muscarinic Autoreceptor-Mediated Inhibition of [3H]Acetylcholine Release in the Rat Isolated Urinary Bladder

Gianluigi D’Agostino, Annalisa Barbieri, Elena Chiossa and Marcello Tonini
Journal of Pharmacology and Experimental Therapeutics November 1997, 283 (2) 750-756;
Gianluigi D’Agostino
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Annalisa Barbieri
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Elena Chiossa
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Marcello Tonini
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Abstract

A pharmacological analysis was carried out in the rat urinary bladder to assess the nature of muscarinic receptors subtypes functionally involved in the negative feedback mechanism regulating acetylcholine (ACh) secretion from postganglionic cholinergic nerve terminals and in smooth muscle contraction. Bladder strips were preincubated with3H-choline, and the electrically evoked [3H]ACh release was detected simultaneously with contraction in the absence of acetylcholinesterase inhibitors. The effects were compared of seven muscarinic antagonists on [3H]ACh secretion (prejunctional effect) and muscle contraction (postjunctional effect). The rank order of postjunctional potencies (−log EC50) for the seven antagonists (atropine > 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) > hexahydrosiladiphenidol hydrochloride (HHSiD) > tripitramine > pirenzepine > AF DX-116 > methoctramine) as well as their postjunctional affinity estimates (pA2) are in keeping with the notion that muscarinic receptors responsible for bladder contraction belong to the M3 subtype. The M3 subtype-preferring 4-DAMP and HHSiD did not discriminate between prejunctional and postjunctional effects. The M2/M4 subtype-preferring antagonists tripitramine, methoctramine and AF-DX 116 were more potent in facilitating the evoked [3H]ACh release than in inhibiting the contractile response. The rank order of prejunctional potencies was atropine > 4-DAMP > tripitramine > HHSiD > methoctramine > AF-DX 116 > pirenzepine, indicating the involvement of M4 receptors. Furthermore, when potency relationship was determined by correlating prejunctional−log EC50 values with published constants for cloned and natives muscarinic receptor subtypes, the correlations were significant for both M4 and M5 subtypes, but the best correlation found (P < .001) was for the M4subtype. These findings suggest that the negative feedback mechanism inhibiting the release of ACh in the rat urinary bladder is mediated by prejunctional autoreceptors of the M4 subtype.

Footnotes

  • Send reprint requests to: Dr. Gianluigi D’Agostino, Institute of Pharmacology, School of Pharmacy, Viale Taramelli 14, I-27100 Pavia, Italy.

  • ↵1 This work was supported in part by a grant from the Italian Ministry for University and Scientific Research (MURST: 60% Project).

  • Abbreviations:
    ACh
    acetylcholine
    TTX
    tetrodotoxin
    HHSiD
    hexahydrosiladiphenidol hydrochloride
    4-DAMP
    4-diphenylacetoxy-N-methylpiperidine methiodide
    EFS
    electrical field stimulation
    • Received March 6, 1997.
    • Accepted July 11, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 2
1 Nov 1997
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OtherAUTONOMIC PHARMACOLOGY

M4 Muscarinic Autoreceptor-Mediated Inhibition of [3H]Acetylcholine Release in the Rat Isolated Urinary Bladder

Gianluigi D’Agostino, Annalisa Barbieri, Elena Chiossa and Marcello Tonini
Journal of Pharmacology and Experimental Therapeutics November 1, 1997, 283 (2) 750-756;

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M4 Muscarinic Autoreceptor-Mediated Inhibition of [3H]Acetylcholine Release in the Rat Isolated Urinary Bladder

Gianluigi D’Agostino, Annalisa Barbieri, Elena Chiossa and Marcello Tonini
Journal of Pharmacology and Experimental Therapeutics November 1, 1997, 283 (2) 750-756;
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