title: Efficacy of a selective histamine H2 receptor agonist, dimaprit, in experimental models of endotoxin shock and hepatitis in mice.
abstract: Dimaprit, a selective histamine H2 receptor agonist, was examined in experimental models of endotoxin shock and hepatitis in mice. Injection of lipopolysaccharide (8 mg/kg i.v.) into Balb/c mice resulted in an elevation of plasma tumor necrosis factor-alpha (TNF-alpha), reaching the maximal level at 1 h post-lipopolysaccharide (1147 U/ml). Oral administration of dimaprit 200 mg/kg, 1 h prior to lipopolysaccharide challenge, inhibited the increase in plasma TNF-alpha by 71% and also the survival rate was increased to 62.5% from 8.3% in the disease control. In a mouse hepatitis model, simultaneous injection of galactosamine (700 mg/kg i.v.) and lipopolysaccharide (3 micrograms/kg i.v.) into Balb/c mice caused an increase in plasma TNF-alpha, peaking at 1 h, followed by an elevation of L-alanine aminotransferase (E.C.2.6.1.2) activity at 4 h onward. Oral administration of dimaprit 200 mg/kg, 1 h prior to galactosamine and lipopolysaccharide, reduced the increase in plasma TNF-alpha by 99% and L-alanine aminotransferase by 82%. In vitro, dimaprit dose dependently inhibited the production of TNF-alpha in mouse peritoneal macrophages and human peripheral blood monocytes stimulated with lipopolysaccharide with IC50 values of 1 microM. The decrease in TNF-alpha production by dimaprit was reversed by cimetidine, a histamine H2 receptor antagonist. Dimaprit dose dependently suppressed TNF-alpha mRNA in human peripheral blood monocytes. These results suggest that activation of the histamine H2 receptor downregulates the production of TNF-alpha, and that histamine may be an important regulator in pathological conditions in which TNF-alpha plays an important role.
authors.affiliation: Department of Medicinal Biology, Pfizer Inc., Aichi, Japan. takaaki@pfizer.co.jp
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: Y
authors.initials: Y
authors.lastname: Ueno
authors.forename: Y
authors.initials: Y
authors.lastname: Goda
authors.forename: A
authors.initials: A
authors.lastname: Nakamura
authors.forename: K
authors.initials: K
authors.lastname: Shinjo
authors.forename: A
authors.initials: A
authors.lastname: Nagahisa
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D015152:Blotting, Northern; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000473:pathology; D017259:Dimaprit / Q000627:therapeutic use*; D005688:Galactosamine; D017442:Histamine Agonists / Q000627:therapeutic use*; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D012772:Shock, Septic / Q000188:drug therapy* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D015415:Biomarkers; D017442:Histamine Agonists; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D000410:Alanine Transaminase; D017259:Dimaprit