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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Acetylcholine-Induced Desensitization of Muscarinic Contractile Response in Guinea Pig Ileum Is Inhibited by Pertussis Toxin Treatment

Frederick J. Ehlert, Khurram Z. Ansari, Darakhshanda Shehnaz, Gregory W. Sawyer and Michael T. Griffin
Journal of Pharmacology and Experimental Therapeutics December 2001, 299 (3) 1126-1132;
Frederick J. Ehlert
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Khurram Z. Ansari
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Darakhshanda Shehnaz
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Gregory W. Sawyer
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Michael T. Griffin
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Abstract

We investigated the effects of pertussis toxin treatment on acetylcholine-induced desensitization of the muscarinic contractile response in guinea pig ileum. Incubation of the isolated ileum with acetylcholine (30 μM) for 20 min caused a decrease in the sensitivity of the ileum to the contractile action of the muscarinic agonist oxotremorine-M. This desensitization was characterized by an increase in the EC50 value of oxotremorine-M without a change in its maximal effect. A maximal 4- to 5-fold increase in the EC50value of oxotremorine-M was measured at the earliest time investigated after acetylcholine treatment (5 min), and normal sensitivity recovered within approximately 20 min after washout of acetylcholine. Treatment of the ileum with pertussis toxin caused a small increase in the contractile response to oxotremorine-M when measured without prior exposure to acetylcholine. After exposure to acetylcholine, little desensitization was observed in ilea that had been treated with pertussis toxin. Pertussis toxin-treatment caused a small increase in oxotremorine-M-mediated phosphoinositide hydrolysis and a large decrease in oxotremorine-M-mediated inhibition of forskolin-stimulated cAMP accumulation in slices of the longitudinal muscle of the ileum. Exposure of the ileum to acetylcholine had no desensitizing effect on the ability of oxotremorine-M to elicit phosphoinositide hydrolysis, indicating that the mechanism for desensitization of the contractile response occurs at a level downstream from the receptor and phosphoinositide hydrolysis. Our results suggest that activation of muscarinic receptors coupled to pertussis toxin-sensitive Gi and Go is required for most of the desensitization observed in this study.

Footnotes

  • This work was supported by National Institutes of Health Grant NS30882.

  • Abbreviations:
    KRB
    Krebs-Ringer-bicarbonate
    Emax
    maximal response
    4-DAMP mustard
    N-2-chloroethyl-4-piperidinyl diphenylacetate
    AF-DX 116
    [[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3b][1,4]-benzodiazepine-6-1
    • Received July 2, 2001.
    • Accepted September 7, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 3
1 Dec 2001
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Acetylcholine-Induced Desensitization of Muscarinic Contractile Response in Guinea Pig Ileum Is Inhibited by Pertussis Toxin Treatment

Frederick J. Ehlert, Khurram Z. Ansari, Darakhshanda Shehnaz, Gregory W. Sawyer and Michael T. Griffin
Journal of Pharmacology and Experimental Therapeutics December 1, 2001, 299 (3) 1126-1132;

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Acetylcholine-Induced Desensitization of Muscarinic Contractile Response in Guinea Pig Ileum Is Inhibited by Pertussis Toxin Treatment

Frederick J. Ehlert, Khurram Z. Ansari, Darakhshanda Shehnaz, Gregory W. Sawyer and Michael T. Griffin
Journal of Pharmacology and Experimental Therapeutics December 1, 2001, 299 (3) 1126-1132;
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