Potent mast cell degranulation and vascular permeability triggered by urocortin through activation of corticotropin-releasing hormone receptors

Urocortin (Ucn) is related to corticotropin-releasing hormone (CRH), and bo th 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. H ere, we report that a concentration of intradermal Ucn as low as 10 nM indu ced dose-dependent rat skin mast cell degranulation and increased vascular permeability. This effect appeared to be equipotent to that of calcitonin g ene-related peptide and neurotensin. Ucn-induced skin vasodilation was inhi bited by pretreatment with the mast cell stabilizer disodium cromoglycate ( cromolyn) and was absent in the mast cell-deficient W/W-v mice. The selecti ve nonpeptide CRH receptor 1 antagonist, antalarmin and the nonselective pe ptide antagonist astressin both reduced vascular permeability triggered by Ucn but not that by Substance P or histamine. In contrast, the peptide anta gonist alpha-helical CRH-(9-41) reduced the effect of all three. The vasodi latory effect of Ucn was largely inhibited by pretreatment with H-1 recepto r antagonists, suggesting that histamine is the major mediator involved in vitro. Neuropeptide depletion of sensory neurons, treatment with the gangli onic blocker hexamethonium, or in situ skin infiltration with the local ane sthetic lidocaine did not affect Ucn-induced vascular permeability, indicat ing 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.