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Corticotropin-Releasing Hormone Causes Vasodilation in Human Skin via Mast Cell-Dependent Pathways

Mothers and Babies Research Centre (R.C., V.L.C., R.S., A.T.B., M.A.R., I.M.R.W.), Hunter Medical Research Institute; Discipline of Reproductive Medicine (A.T.B.), University of Newcastle; and Division of Obstetrics and Gynaecology (M.A.R.) and Neonatal Intensive Care Unit (I.M.R.W.), John Hunter Hospital, Newcastle NSW 2310, Australia

Address all correspondence and requests for reprints to: Dr. Ian M.R. Wright, Neonatal Intensive Care Unit, John Hunter Hospital, Locked Bag #1, Hunter Region Mail Centre, Newcastle, NSW 2310, Australia. E-mail: iwright{at}mail.newcastle.edu.au.

CRH plays a central role as a mediator of the hypothalamic-pituitary-adrenal axis and stress response and is a potent vasodilator. Previously, we have shown that CRH causes a gender-specific vasodilation in human skin, although the mechanism by which CRH operates is unclear. CRH causes mast cell degranulation in rat skin. As such, histamine and other mast cell-derived factors may be indirectly responsible for the vasodilatory effects of CRH, although CRH is also known to act directly on the vasculature.

CRH-induced vasodilation in human skin was examined using laser Doppler flowmetry and iontophoresis in adult females. CRH (1 nM) was administered iontophoretically to the forearm, and blood flow was measured simultaneously in the same area by laser Doppler. CRH-induced dilation of the skin microvasculature was significantly reduced in the presence of the mast cell degranulation inhibitor, sodium cromoglycate, the histamine H₁-antagonist, promethazine, or the H₂-antagonist, ranitidine. CRH-induced dilation was also significantly reduced in the presence of the nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester, or the cyclooxygenase inhibitor, piroxicam.

These findings provide novel evidence that CRH-induced vasodilation in human skin occurs via mast cell degranulation and is principally mediated by histamine and, to a lesser extent, by prostacyclin and nitric oxide.

This study was funded by the John Hunter Children’s Hospital Research Foundation, Buttercup Babies Appeal, Research Management Committee of the University of Newcastle, and the John Hunter Charitable Trust Fund.

Abbreviations: GEE, Generalized estimating equation; D-NAME, N-nitro-D-arginine methyl ester; L-NAME, N-nitro-L-arginine methyl ester; NO, nitric oxide; PGI₂, prostacyclin; POMC, pro-opiomelanocortin; PU, perfusion unit.

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