title: Histamine Induces Vascular Hyperpermeability by Increasing Blood Flow and Endothelial Barrier Disruption In Vivo.
abstract: Histamine is a mediator of allergic inflammation released mainly from mast cells. Although histamine strongly increases vascular permeability, its precise mechanism under in vivo situation remains unknown. We here attempted to reveal how histamine induces vascular hyperpermeability focusing on the key regulators of vascular permeability, blood flow and endothelial barrier. Degranulation of mast cells by antigen-stimulation or histamine treatment induced vascular hyperpermeability and tissue swelling in mouse ears. These were abolished by histamine H1 receptor antagonism. Intravital imaging showed that histamine dilated vasculature, increased blood flow, while it induced hyperpermeability in venula. Whole-mount staining showed that histamine disrupted endothelial barrier formation of venula indicated by changes in vascular endothelial cadherin (VE-cadherin) localization at endothelial cell junction. Inhibition of nitric oxide synthesis (NOS) by L-NAME or vasoconstriction by phenylephrine strongly inhibited the histamine-induced blood flow increase and hyperpermeability without changing the VE-cadherin localization. In vitro, measurements of trans-endothelial electrical resistance of human dermal microvascular endothelial cells (HDMECs) showed that histamine disrupted endothelial barrier. Inhibition of protein kinase C (PKC) or Rho-associated protein kinase (ROCK), NOS attenuated the histamine-induced barrier disruption. These observations suggested that histamine increases vascular permeability mainly by nitric oxide (NO)-dependent vascular dilation and subsequent blood flow increase and maybe partially by PKC/ROCK/NO-dependent endothelial barrier disruption.
authors.affiliation: Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Ashina
authors.affiliation: Department of Animal Radiology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Tsubosaka
authors.affiliation: Department of Animal Radiology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Animal Radiology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Omori
authors.affiliation: Department of Animal Radiology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hori
authors.affiliation: Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozaki
authors.affiliation: Department of Animal Radiology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Murata
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D004431:Ear, External / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006632:Histamine / Q000378:metabolism / Q000494:pharmacology*; D017442:Histamine Agonists / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D017442:Histamine Agonists; D011725:Pyridines; D011969:Receptors, Histamine H1; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D006632:Histamine; C006183:2-(2-aminoethyl)pyridine; D019001:Nitric Oxide Synthase; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D019331:NG-Nitroarginine Methyl Ester