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Research ArticleArticle

Potent Mast Cell Degranulation and Vascular Permeability Triggered by Urocortin Through Activation of Corticotropin-Releasing Hormone Receptors

Leena K. Singh, William Boucher, Xinzhu Pang, Richard Letourneau, Dimitri Seretakis, Marlon Green and Theoharis C. Theoharides
Journal of Pharmacology and Experimental Therapeutics March 1999, 288 (3) 1349-1356;
Leena K. Singh
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William Boucher
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Xinzhu Pang
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Richard Letourneau
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Dimitri Seretakis
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Marlon Green
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Theoharis C. Theoharides
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Abstract

Urocortin (Ucn) is related to corticotropin-releasing hormone (CRH), and both are released in the brain under stress where they stimulate CRH 1 and 2 receptors (CRHR). Outside the brain, they may have proinflammatory actions through activation of mast cells, which are located perivascularly close to nerve endings and degranulate in response to acute psychological stress. Here, we report that a concentration of intradermal Ucn as low as 10 nM induced dose-dependent rat skin mast cell degranulation and increased vascular permeability. This effect appeared to be equipotent to that of calcitonin gene-related peptide and neurotensin. Ucn-induced skin vasodilation was inhibited by pretreatment with the mast cell stabilizer disodium cromoglycate (cromolyn) and was absent in the mast cell-deficient W/Wv mice. The selective nonpeptide CRH receptor 1 antagonist, antalarmin and the nonselective peptide antagonist astressin both reduced vascular permeability triggered by Ucn but not that by Substance P or histamine. In contrast, the peptide antagonist α-helical CRH-(9–41) reduced the effect of all three. The vasodilatory effect of Ucn was largely inhibited by pretreatment with H1 receptor antagonists, suggesting that histamine is the major mediator involved in vitro. Neuropeptide depletion of sensory neurons, treatment with the ganglionic blocker hexamethonium, or in situ skin infiltration with the local anesthetic lidocaine did not affect Ucn-induced vascular permeability, indicating that its in situ effect was not mediated through the peripheral nervous system. These results indicate that Ucn is one of the most potent triggers of rat mast cell degranulation and skin vascular permeability. This effect of Ucn may explain stress-induced disorders, such as atopic dermatitis or psoriasis, and may lead to new forms of treatment.

Footnotes

  • Send reprint requests to: T. C. Theoharides, Ph.D, M.D, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. E-mail: ttheoharides{at}infonet.tufts.edu

  • ↵1 This work was supported by a grant from Kos Pharmaceuticals (FL) to T.C.T..

  • Abbreviations:
    ACTH
    adrenocorticotropic hormone
    CRH
    corticotropin-releasing hormone
    BSA
    bovine serum albumin
    CRHR
    corticotropin-releasing hormone receptor
    Ucn
    urocortin
    C48/80
    compound 48/80
    CGRP
    calcitonin gene-related peptide
    ES
    electrical stimulation
    NT
    neurotensin
    SP
    Substance P
    VIP
    vasoactive intestinal peptide
    • Received June 24, 1998.
    • Accepted October 9, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 3
1 Mar 1999
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Research ArticleArticle

Potent Mast Cell Degranulation and Vascular Permeability Triggered by Urocortin Through Activation of Corticotropin-Releasing Hormone Receptors

Leena K. Singh, William Boucher, Xinzhu Pang, Richard Letourneau, Dimitri Seretakis, Marlon Green and Theoharis C. Theoharides
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 1349-1356;

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Research ArticleArticle

Potent Mast Cell Degranulation and Vascular Permeability Triggered by Urocortin Through Activation of Corticotropin-Releasing Hormone Receptors

Leena K. Singh, William Boucher, Xinzhu Pang, Richard Letourneau, Dimitri Seretakis, Marlon Green and Theoharis C. Theoharides
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 1349-1356;
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