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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Roles of Substance P Receptors in Human Colon Circular Muscle: Alterations in Diverticular Disease

Lu Liu, Fei Shang, Irit Markus and Elizabeth Burcher
Journal of Pharmacology and Experimental Therapeutics August 2002, 302 (2) 627-635; DOI: https://doi.org/10.1124/jpet.102.034702
Lu Liu
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Fei Shang
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Irit Markus
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Elizabeth Burcher
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Abstract

The characteristics of [125I]Bolton-Hunter[Sar9,Met(O2)11]substance P ([125I]BH-SarSP) binding were investigated in membranes of human ascending, transverse, distal, and sigmoid colon circular muscle. Binding of [125I]BH-SarSP was of high affinity (KD = 68 nM) and low capacity (Bmax = 0.31 fmol/mg of wet weight tissue), and showed no regional differences. [125I]BH-SarSP binding was inhibited by SP ≈ [Pro9]SP ≥ (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP99994) ≫ neurokinin (NK) A ≥ neuropeptide γ > [Lys5,MeLeu9,Nle10]-NKA(4–10) ≈ (S)-N-methyl-N[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) butyl]benzamide (SR48968) ≫ senktide, suggesting binding to NK-1 sites. Most agonists seemed to bind to two sites. In autoradiographic studies, dense binding for [125I]BH-SarSP was associated with submucosal and longitudinal muscle blood vessels, and the submucosal margin of circular muscle (corresponding to interstitial cells of Cajal), with moderate binding over most of the circular muscle. In normal colon circular muscle strips, [Pro9]SP was almost ineffective, and SP caused contractions with pD2 values of 5.3 to 5.7. No regional differences were observed in potency or efficacy. Responses to SP were inhibited by the NK-2 receptor antagonist SR48968, but not by NK-1 antagonist CP99994, indicating the involvement of NK-2 rather than NK-1 receptors. Atropine significantly inhibited contractions induced by SP, indicating a minor cholinergic component. Contractile responses to SP were considerably reduced in preparations from patients with diverticular disease, and marginally reduced in ulcerative colitis compared with control. This study clearly demonstrates an NK-1 binding site on human colon circular muscle, but its role in this tissue remains unclear and may not involve contractile mechanisms. The attenuated contractility in specimens with diverticular disease may reflect disease-related alterations of the tachykinin receptor system.

Footnotes

  • DOI: 10.1124/jpet.102.034702

  • Abbreviations:
    SP
    substance P
    NK
    neurokinin
    NPγ
    neuropeptide γ
    Ach
    acetylcholine
    ICC
    interstitial cells of Cajal
    [125I]BH-SarSP
    [125I]Bolton-Hunter [Sar9,Met(O2)11]substance P
    BSA
    bovine serum albumin
    ANOVA
    analysis of variance
    CP99994
    (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine
    SR48968
    (S)-N-methyl-N[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) butyl]benzamide
    • Received February 24, 2002.
    • Accepted April 15, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 302 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 302, Issue 2
1 Aug 2002
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Roles of Substance P Receptors in Human Colon Circular Muscle: Alterations in Diverticular Disease

Lu Liu, Fei Shang, Irit Markus and Elizabeth Burcher
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 627-635; DOI: https://doi.org/10.1124/jpet.102.034702

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Roles of Substance P Receptors in Human Colon Circular Muscle: Alterations in Diverticular Disease

Lu Liu, Fei Shang, Irit Markus and Elizabeth Burcher
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 627-635; DOI: https://doi.org/10.1124/jpet.102.034702
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