EFFICACY OF A SELECTIVE HISTAMINE H-2-RECEPTOR AGONIST, DIMAPRIT, IN EXPERIMENTAL-MODELS OF ENDOTOXIN-SHOCK AND HEPATITIS IN MICE

Dimaprit, a selective histamine H-2 receptor agonist, was examined in experimental models of endotoxin shock and hepatitis in mice. Injectio n of lipopolysaccharide (8 mg/kg i.v.) into Balb/c mice resulted in an elevation af plasma tumor necrosis factor-alpha (TNF-alpha), reaching the maximal level at 1 h post-lipopolysaccharide (1147 U/ml). Oral ad ministration of dimaprit 200 mg/kg, 1 h prior to lipopolysaccharide ch allenge, inhibited the increase in plasma TNF-alpha by 71% and also th e survival rate was increased to 62.5% from 8.3% in the disease contro l. In a mouse hepatitis model, simultaneous injection of galactosamine (700 mg/kg i.v.) and lipopolysaccharide (3 mu g/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 a t 4 h onward. Oral administration of dimaprit 200 mg/kg, 1 h prior to galactosamine and lipopolysaccharide, reduced the increase in plasma T NF-alpha by 99% and L-alanine aminotransferase by 82%. In vitro, dimap rit dose dependently inhibited the production of TNF-alpha in mouse pe ritoneal macrophages and human peripheral blood monocytes stimulated w ith lipopolysaccharide with IC50 values of 1 mu M. The decrease in TNF -alpha production by dimaprit was reversed by cimetidine, a histamine H-2 receptor antagonist. Dimaprit dose dependently suppressed TNF-alph a mRNA in human peripheral blood monocytes. These results suggest that activation of the histamine H-2 receptor downregulates the production of TNF-a, and that histamine may be an important regulator in patholo gical conditions in which TNF-alpha plays an important role. (C) 1997 Elsevier Science B.V.