Suppression of ischaemia-induced cytokine release by dimaprit and amelioration of liver injury in rats.

Inflammatory reactions play an important role in ischaemia/reperfusion injury in various organs. Since histamine H(4) action has been shown to prevent the development of ischaemia/reperfusion liver injury, we examined the effects of dimaprit, a histamine H(2)/H(4) receptor agonist, on ischaemia-induced cytokine release and liver damage. Male Wistar rats (300 g) were subjected to warm ischaemia for 30 min. by occlusion of the left portal vein and hepatic artery under halothane anaesthesia. Saline or dimaprit (20 mg/kg, subcutaneously) was injected immediately after reperfusion of blood flow. Transient ischaemia provoked severe liver damage 24 hr after reperfusion, and the plasma concentrations of alanine transaminase and aspartate transaminase were 4600 IU/l and 13,200 IU/l, respectively. The values in the dimaprit group were 55% and 46% of those in control animals, respectively. Dimaprit also reduced the infarct size to 50%. Liver ischaemia markedly increased interleukin-12 levels 2-24 hr after reperfusion. The dimaprit treatment depressed the values to 40-64% of those in the corresponding control group 4-24 hr after reperfusion. Since interleukin-12 facilitates cell-mediated cytotoxicity, the protective effect of dimaprit may be attributed to regulation of cytokine release during reperfusion.

Histamine signaling through the H(2) receptor in the Peyer's patch is important for controlling Yersinia enterocolitica infection.

Enteric pathogens such as Yersinia enterocolitica readily colonize and induce disease within the lymphatic tissues of the small intestine. To gain a comprehensive view of the host response to pathogens within these tissues, we determined the transcriptional profiles of intestinal lymphatic tissue infected with Y. enterocolitica. Expression analysis using Affymetrix GeneChips revealed a complex host response in the Peyer's patches and mesenteric lymph nodes after oral infection with Y. enterocolitica. Interestingly, histidine decarboxylase (Hdc) was significantly up-regulated in response to Y. enterocolitica infection. HDC is the enzyme solely responsible for the production of the biogenic amine histamine. Although histamine is well known for its role in allergy and for its effects on immunity and inflammation, little is known about its role or specific histamine receptors during the host response to bacterial infection. In this study, we provide evidence that histamine signaling through the histamine H(2) but not the H(1) receptor is important for controlling Y. enterocolitica infection within the Peyer's patches and mesenteric lymph nodes of mice.

Activation of histamine H2 receptors ameliorates experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis, is an autoimmune, demyelinating disease of the CNS. Pro-inflammatory cytokines (e.g. tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-12) and reactive oxygen species are implicated in promoting EAE. Since histamine H(2) receptor activation suppresses production of O(2)*-, TNF-alpha, and IL-12 by inflammatory cells, we tested the hypothesis that dimaprit, an H(2) agonist, would reduce the clinical severity and pathology of EAE. Dimaprit treatment significantly reduced clinical signs compared to vehicle in both C57BL/6 and iNOS deficient EAE mice. Furthermore, dimaprit significantly reduced CNS staining for lectin-positive macrophages and decreased extravasated albumin staining, an indicator of blood-brain barrier leakage. These data provide a rationale for exploring H2 receptor activation for therapeutic value in multiple sclerosis.

Efficacy of a selective histamine H2 receptor agonist, dimaprit, in experimental models of endotoxin shock and hepatitis in mice.

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.

Histamine N-methyltransferase inhibitor potentiates histamine- and antigen-induced airway microvascular leakage in guinea pigs.

BACKGROUND: Histamine N-methyltransferase (HMT) modulates histamine- and antigen-induced bronchoconstriction. However, it is unclear whether vascular permeability evoked by an allergic reaction can be exaggerated by inhibition of HMT activity. METHODS: We studied the effects of intravenously injected SKF 91488, a specific HMT inhibitor, on increases in plasma extravasation induced by intravenously injected histamine in unsensitized guinea pigs and by intravenously injected ovalbumin antigen in guinea pigs sensitized to ovalbumin in vivo with Evans blue dye as a marker. RESULTS: Pretreatment with SKF 91488 shifted, in a dose-dependent fashion, the dose-response curves of the leakage of dye to histamine to lower concentrations in the trachea, main bronchi, and nasal mucosa. Likewise, pretreatment with SKF 91488 (20 mg/kg intravenously) significantly increased the leakage of dye induced by ovalbumin antigen (200 micrograms/kg intravenously) in three parts of the airway (p < 0.05). In contrast to SKF 91488, intravenously injected aminoguanidine, a specific inhibitor of diamine oxidase (16 mg/kg intravenously), did not alter the leakage of dye induced by histamine (from 0.001 microgram/kg to 10 micrograms/kg intravenously) (p < 0.20). HMT activities were observed in the nasal mucosa, as well as in the trachea and main bronchi, as shown in a previous study. CONCLUSION: These findings suggest that HMT modulates the effects of exogenous histamine and endogenously released histamine induced by antigen challenge on plasma extravasation in the airway in guinea pigs in vivo.

[The relationship between H2 receptor and the pathogenesis of bronchial asthma in guinea-pigs].

UNLABELLED: H2 receptor (H2R) is one of the three histamine receptor subtypes. In order to explore the relationship between H2R and the pathogenesis of bronchial asthma, we investigated the effects of H2R agonist impromidine on guinea-pig isolated tracheal smooth muscle and the effects of dimaprit on the lung function of guinea-pigs provoked by antigen. RESULTS: (1) Impromidine (10(6) mol/L) relaxed partly the guinea-pig isolated tracheal spirals contricted by histamine challenge. After pretreating the spirals with impromidine, the maximum response to histamine was reduced in a dose-dependent manner and the cumulative dose-response curve to histamine was shifted to right. (2) Dimaprit (3mg/kg) given by intravenous injection protected the lung function from damage caused by antigen. These results suggest that H2R agonist produces relaxation of guinea-pig tracheal smooth muscle and inhibits the release of inflammatory mediators in anaphylactic reaction. We concluded that H2R plays some protective roles in the pathogenesis of bronchial asthma.