title: Effects of histamine 2 receptor antagonists on endothelial-neutrophil adhesion and surface expression of endothelial adhesion molecules induced by high glucose levels.
abstract: Neutrophil-endothelial adhesion is a crucial step in vascular inflammation and is recognized as a direct cause of serious atherosclerosis-mediated diseases. We previously demonstrated that high concentrations of glucose increased adhesion in a protein kinase C (PKC)-dependent manner within 48 h of administration by increasing the surface expression of endothelial adhesion molecules. In this study, we focused on the effects of histamine 2 receptor antagonists on endothelial-neutrophil adhesion and on the surface expression of endothelial adhesion molecules mediated by high glucose levels. Histamine 2 receptor antagonists have pleiotropic effects; they not only block the secretion of gastric acid, but also inhibit cell-cell adhesion, resulting in inhibition of metastasis. However, relevant mechanisms of action are not yet fully understood. Of three histamine 2 receptor antagonists (cimetidine, ranitidine, and famotidine), only cimetidine significantly attenuated adhesion mediated by 48-h incubation with 27.8 mM glucose. Cimetidine was found to decrease the surface expression of endothelial adhesion molecules intercellular adhesion molecule-1 and P-selectin, but not E-selectin. To determine the effects of cimetidine on intracellular level, we examined the effects of cimetidine on PKC-induced changes in adhesion, as well as the effects of nitric oxide (NO) synthase inhibitors on cimetidine. We found that NO synthase inhibitors reduced the inhibitory effects of cimetidine, whereas cimetidine did not affect adhesion mediated by a PKC activator. These data suggest that cimetidine acts directly on endothelial cells to inhibit high-glucose-induced expression of adhesion molecules and neutrophil adhesion mediated by increasing endothelial NO production, but not by inhibiting PKC.
authors.affiliation: Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Naotsuka
authors.initials: N
authors.lastname: Okayama
authors.forename: Kenro
authors.initials: K
authors.lastname: Imaeda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okouchi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Omi
authors.forename: Seiji
authors.initials: S
authors.lastname: Imai
authors.forename: Masaya
authors.initials: M
authors.lastname: Akao
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takeda
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hukutomi
authors.forename: Makoto
authors.initials: M
authors.lastname: Itoh
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002927:Cimetidine / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D015738:Famotidine / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006801:Humans; D009504:Neutrophils / Q000502:physiology*; D011899:Ranitidine / Q000494:pharmacology*; D014471:Umbilical Veins
chemical_list: D006635:Histamine H2 Antagonists; D015738:Famotidine; D002927:Cimetidine; D011899:Ranitidine; D005947:Glucose