The effects of H2-receptor antagonists on anaphylaxis in the guinea-pig

Histamine has been shown to inhibit a variety of immune responses including the antigen-induced, IgE mediated, release of histamine from sensitized human leucocytes and from sensitized monkey and dog mast cells. The inhibitory action of histamine appears to be mediated by action at a histamine H₂-receptor. In in vitro experiments the H₂-receptor antagonist metiamide has been shown to block this histamine effect and it has been suggested that H₂-receptor antagonists could intensify immediate hypersensitivity reactions in vivo.The effects of the H₂-receptor antagonist metiamide and cimetidine have been studied in in vitro and in vivo models of anaphylaxis in the guinea-pig. The amount of extracellular histamine found after antigen challenge is greater when an H₂-receptor antagonist is present during the incubation of mast cells with antigen. Bronchoconstriction induced by antigen in sensitized guinea-pig is exacerbated only by high doses of cimetidine. Possible explanations for the mechanism of action involved are discussed.     

A species comparison of the histamine H2-receptor on mast cells and basophils

The histamine H₂-agonist dimaprit was employed in experiments to investigate the role of H₂-receptors in mediator release systems from the rat, guinea-pig and man. Whereas inhibition of histamine release by dimaprit was observed in all 3 species, this effect appeared not always to be related to H₂-receptor occupancy. Although the data in general support previous evidence for the presence of H₂-receptors on human basophils and guinea-pig mast cells, the use of dimaprit as a pure H₂-agonist in these studies is questioned. No evidence for H₂-receptors on rat mast cells was obtained.     

Mast cell receptors controlling histamine release: Influences on the mode of action of drugs used in the treatment of adverse drug reactions

Summary In drug-induced allergic diseases of the immediate type (anaphylactic and anaphylactoid reactions), the primary target cells are tissue mast cells, which discharge their granular content upon interaction with different secretagogues (immunological releasers; histamine liberators) on specific plasma membrane receptors.Experiments are reviewed here which report that IgE-mediated histamine release from mast cells, and the secretion of histamine induced by non-immunological secretagogues (dextran; compound 48/80; acetylcholine) are blocked by beta-adrenoceptor and H₂-receptor agonists, their inhibiting effect being surmountable by beta-adrenoceptor blocking drugs and by anti-H₂-antihistamines. Specific radioligands ([³H]-dihydroalprenolol; [³H]-cimetidine) binding to rat mast cell membranes points to the possibility that inhibition of histamine release is brought about by the activation of mast cell beta-adrenoceptors and H₂-receptors.Drugs used in therapy of anaphylactic or anaphylactoid reactions may act either on tissue receptors, competing with released mediators, or by inhibiting the release of allergic mediators from mast cells, on activation of specific receptors located in mast cell plasma membranes.     

Inhibitory effect of the stereoisomers of dimethindene maleate (Fenistil®) on histamine release from rat peritoneal mast cells

Dimethindene maleate (DM) (Fenistil^R) is a potent antihistamine with a prolonged duration of action. In the present study, the racemic (±) form of DM and its individual (+) and (−) optical isomers were shown to be weak or non-releasers of histamine from rat peritoneal mast cells and to produce a comparable, dose-dependent inhibition of anti-IgE-induced histamine release from the same cell type. As such, the inhibitory activity of DM on the mast cell is probably due to the stabilization of this cell type rather than an interaction with the H₁-receptor.

     

Inhibitory effect of the stereoisomers of dimethindene maleate (Fenistil?) on histamine release from rat peritoneal mast cells

Dimethindene maleate (DM) (Fenistil^R) is a potent antihistamine with a prolonged duration of action. In the present study, the racemic (±) form of DM and its individual (+) and (–) optical isomers were shown to be weak or non-releasers of histamine from rat peritoneal mast cells and to produce a comparable, dose-dependent inhibition of anti-IgE-induced histamine release from the same cell type. As such, the inhibitory activity of DM on the mast cell is probably due to the stabilization of this cell type rather than an interaction with the H₁-receptor.     

Histamine increases anti-CD3 induced IL-5 production of TH2-type T cells via histamine H2-receptors

Besides its proinflammatory functions histamine released from basophils and mast cells during immediate-type hypersensitivity reactions is known to inhibit several lymphocyte functions like IL-2 and -IFN production. Recently, it has been shown that T helper cells of type 2 phenotype (T_H2) represent the T cell fraction which may play a pivotal role in the promotion of the allergic inflammatory eosinophilic late-phase reaction by secretion of cytokines, especially IL-4 and IL-5. We have investigated the effect of histamine on anti-CD3 induced IL-4 and IL-5 production by T_H2 cells. Histamine in concentrations between 10^–7 and 10^–5 mol/l concentration-dependently increased anti-CD3 induced IL-5 production up to 120%, whereas IL-4 production was not affected. The activity of histamine in increasing IL-5 production was mimicked by the H₂-receptor agonist dimaprit. Histamine induced increase in IL-5 production was inhibited by histamine H₂-receptor antagonists, but remained unaffected by H₁- or H₃-receptor antagonists. Administration of forskolin which directly stimulates the production of cAMP, the second messenger of the H₂-receptor, also resulted in an increase in anti-CD3 induced IL-5 production. These results indicate that the histamine-mediated increase in anti-CD3 induced IL-5 production is mediated via H₂-receptors. Consequently, histamine released from mast cells and basophils during the early-phase allergic reaction may act as an important stimulatory signal for the initiation of the allergic inflammatory late-phase reaction by increasing local IL-5 production of allergen triggered T_H2 cells.     

The source and action of histamine in the isolated guinea-pig gallbladder

We have investigated the effects of histamine on motility of the gallbladder and characterized the receptor types involved. Histamine and the histamine H₁-receptor agonist, 2-thiazolylethylamine (2-TEA) contracted the isolated guinea-pig gallbladder strip in a dose dependent manner. The contractile response to histamine was shifted to the right by the H₁-receptor antagonist, mepyramine. In pre-contracted gallbladder strips, the H₂-receptor agonist dimaprit reduced the tension generated in a dose dependent fashion. The histamine H₂-receptor antagonist, ranitidine shifted the histamine concentration effect curve to the left and attenuated the dose dependent relaxations elicited at high concentrations. The histamine H₃-receptor agonist, (R)--methylhistamine (RMHA) elicited dose dependent contraction of the tissue which was significantly inhibited in the presence of mepyramine. The effects of electrical field stimulation (EFS) on the strips were not significantly altered by the presence of RMHA (10^–10–10^–7 M) indicating little pre-synaptic H₃ activity in this tissue. Histamine immunoreactivity (IR) was detected in gallbladder whole mount preparations of the mucosa and the muscularis/serosa. The histamine IR appeared cell bound in cells of varying morphological characteristics but no IR was detected in nerve fibres or cell bodies (ganglia). Alcian blue staining was consistent with the distribution of histamine IR cells as mast cells. The results indicate that histamine is distributed in the guinea-pig gallbladder and it can regulate contractile activity via activation of H₁ and H₂ but not H₃ receptors.     

Flush induced by fluoroquinolones in canine skin

The flush induced by two fluoroquinolone antibacterial agents, balofloxacin and ofloxacin, was studied in beagle dogs. Intradermal injection of the fluoroquinolones at concentrations above 10^–5M produced a localized flushed area. The flush responses to fluoroquinolones were inhibited by co-administration with H₂-antagonist(s) (ranitidine or cimetidine), but not with H₁-antagonist(s) (mepyramine or chlorpheniramine). Similar inhibitory effects of these H₂-antagonists were observed for the response to histamine. The flush responses to fluoroquinolones were inhibited by a local pretreatment with compound 48/80 administered to deplete the local stores of mast cell-bound histamine. When the fluoroquinolones were orally administered at a dose of 400 mg/kg, the concentration of histamine in plasma was increased, being accompanied by systemic erythema. These results indicate that the flush induced by fluoroquinolones is mediated by histamine release from canine cutaneous mast cells and H₂-receptor stimulation.     

Species differences in histamine receptors in the vas deferens

Histamine, specific H₁-and H₂-receptor agonists in conjunction with specific H₁-and H₂-receptor antagonists and other types of classical antagonists were used to characterize histamine receptors in the vasa deferentia of mice, rats and guinea pigs. The H₁-receptor mediates contraction while the H₂-receptor produces inhibition. There were marked qualitative and quantitative differences in the distribution of the two types of histamine receptors in the vas deferens of different species. Results indicate that mouse and rat vas deferens contain an inhibitory H₂-receptor, but virtually no excitatory H₁-receptor. In contrast, guinea pig vas deferens contained an excitatory H₁-receptor but was essentially devoid of an inhibitory H₂-receptor. The rank order of relative potencies of various agonists as well as the calculated pA ₂ values of cimetidine in the mouse and rat vas deferens suggest that the two species probably have the same H₂-receptor. High concentrations of histamine and 2-methyl histamine have a stimulant action in the mouse and rat vas deferens which was secondary to release of endogenous noradrenaline rather than to the stimulation of an excitatory H₁-receptor.     

A modulation of the anaphylactic basophil histamine release by selective H2 histamine agonists

Two selective H₂-histamine agonists, dimaprit and impromidine, have been tested for their action on histamine release from human basophils and rat mast cells.IgE-mediated basophil histamine release was inhibited by stimulation of histamine H₂-receptors. However, differences between the actions of both dimaprit and impromidine were noticed. Both impromidine and dimaprit had no specific effect on 48/80-induced histamine release from rat mast cells, although the latter in higher concentrations either slightly increased spontaneous histamine release or non-specifically inhibited compound 48/80-induced release.The results are consistent with the view that activation of adenylate cyclase via H₂-histamine receptors might be an important regulatory mechanism of histamine release from human basophils but not from rat mast cells.     

Evidence of mast-cell histamine being mitogenic in intact tissue

We have reported previously that secretion by connective tissue mast cells (MCs) causes mitogenesis in adjacent cells in diverse rat tissues.In cultured rat mesentery there was a spontaneous release of about 45% of the histamine in 2 days, and a spontaneous marked increase in basal proliferation of the mesentery. The MC secretagogues, compound 48/80 and polymyxin B, released additional histamine and stimulated mitogenesis further. In contrast, 48/80 added to cultures of guinea-pig mesentery, the MC of which are unresponsive to the drug, did not affect the basal proliferation. However, exogenous histamine at 10^–10 M mitogenically stimulated the cultured guinea-pig mesentery. A histmaine H₂-receptor antagonist, which itself was mitogenically inert, significantly suppressed the 48/80-induced MC-mediated mitogenesis in rat mesenteryin vivo andin vitro. On the other hand, a histamine H₁-receptor antagonist did not affect this MC-mediated mitogenesis in rat.Our findings indicate that histamine is one of possibly several mitogens which are released or activated by the secreting MC.Supported by the Swedish Medical Research Council, project 5842.     

Inhibitory effect of interleukin-2 on histamine release from rat mast cells

Interleukin-2 (IL-2) inhibited histamine release from rat mast cells induced by compound 48/80 in a concentration-dependent manner. The inhibitory effect of IL-2 on histamine release was also dependent on the length of the incubation period; the maximum inhibition was achieved at 8 h after IL-2 addition. Furthermore, IL-2 inhibited not only IP₃ production but also⁴⁵Ca uptake in mast cells stimulated by compound 48/80. Since IL-2 enhanced [³H]-leucine uptake into mast cells, this suggests that protein synthesis may be related in some way with the inhibition of histamine release. IL-2 treatment augmented the synthesis of a protein having a molecular weight of approximately 35 kDa. From Western blotting analysis, it became clear that the production of lipocortin-I was augmented in rat mast cells by IL-2 treatment. The present study shows that IL-2 induces the synthesis of lipocortin-I in mast cells and that lipocortin-I may play some role in inhibiting histamine release from mast cells.     

Inhibitory effect of interleukin-2 on histamine release from rat mast cells

Interleukin-2 (IL-2) inhibited histamine release from rat mast cells induced by compound 48/80 in a concentration-dependent manner. The inhibitory effect of IL-2 on histamine release was also dependent on the length of the incubation period; the maximum inhibition was achieved at 8 h after IL-2 addition. Furthermore, IL-2 inhibited not only IP₃ production but also⁴⁵Ca uptake in mast cells stimulated by compound 48/80. Since IL-2 enhanced [³H]-leucine uptake into mast cells, this suggests that protein synthesis may be related in some way with the inhibition of histamine release. IL-2 treatment augmented the synthesis of a protein having a molecular weight of approximately 35 kDa. From Western blotting analysis, it became clear that the production of lipocortin-I was augmented in rat mast cells by IL-2 treatment. The present study shows that IL-2 induces the synthesis of lipocortin-I in mast cells and that lipocortin-I may play some role in inhibiting histamine release from mast cells.     

Pathophysiological significance of the distribution of histamine receptor sub-types: a proposed dual role for histamine in inflammation and Type I hypersensitivity reactions

The pathophysiological significance of histaminergic receptors located on the membranes of immunocompetent cells is reviewed. H₂-receptor agonists decrease the immunological histamine release from isolated serosal mast cells and from isolated hearts taken from actively sensitised guinea-pigs. Histamine and H₂-receptor agonists inhibit the generation of superoxide anion from human neutrophils activated by FMLP and by substance P.These observations lend further support to the hypothesis of an immunodepression exerted by the activation of H₂-receptors, which can be converted to immunostimulation by treatment with H₂-receptor antagonists.     

A place for free radicals in platelet-derived histamine releasing factor (PDHRF) and evidence that histaminergic receptors modulate platelet aggregation

The release of histamine from rat serosal mast cells induced by coincubation with resting and activated human platelets, or by exposure of mast cells to supernatants obtained from activated platelets, is significantly reduced by anti-free radical interventions, and is coupled with the generation of membrane lipid peroxidation products. These results suggest free radical participation in the activity of PDHRF. Human platelets possess specific binding sites for an H₁-receptor antagonist, suggesting that H₁-receptors could modulate the intracellular calcium levels in a pro-aggregatory fashion.     

Mast cell and neutrophil interactions: A role for superoxide anion and histamine

Histamine inhibits superoxide anion (O ₂ ^– ) production from human neutrophils stimulated by N-formylmethionlyleucyl-phenylalanine (FMLP). The effects of histamine are dose-dependent and competitively antagonized by cimetidine. When passively sensitized rat serosal mast cells and human neutrophils are mixed together, O ₂ ^– production from FMLP-activated granulocytes is significantly reduced, following mast cell degranulation by acetylcholine. These inhibitory effects can be counteracted by cimetidine. Exposure of non-sensitized rat mast cells to FMLP-stimulated human neutrophils causes histamine release. These results suggest bidirectional control mechanisms between mast cells and neutrophils, that further stress the role of histamine in regulating inflammatory processes.     

Antiallergic Effect of Epinastine (WAL 801 CL) on Immediate Hypersensitivity Reactions: (I) Elucidation of the Mechanism for Histamine Release Inhibition

Abstract

Epinastine caused an inhibition of histamine release from rat peritoneal mast cells induced by both antigen-antibody reaction and compound 48/80. Epinastine was similarly effective in inhibiting compound 48/80-induced histamine release not only from isolated rat peritoneal mast cells but also from rat mesenterial pieces. Also, histamine release from lung pieces obtained from actively sensitized guinea pigs after exposure to antigen challenge was markedly inhibited by epinastine. The drug was effective in inhibiting not only Ca²⁺ uptake into lung mast cells in actively sensitized guinea pigs but also Ca²⁺ release from the intracellular Ca store of rat peritoneal mast cells exposed to both compound 48/80 and substance P. No significant changes were observed in phosphodiesterase activity in rat peritoneal mast cells treated with epinastine, while adenylate cyclase activity was augmented by epinastine. Epinastine has no inhibitory effect on histamine release induced by Ca²⁺ or IP3 from permeabilized mast cells. However, the drug significantly and dose-dependently suppressed calmodulin activity suggesting that histamine release inhibition due to epinastine may be partly attributable to Ca²⁺-calmodulin dependent process(es). The drug caused no visible changes in thermodynamic behavior of lipids, either in order parameter or in differential scanning calorimetry, indicating that the drug has no influence on membrane fluidity.     

Characterization of an adenylate cyclase system sensitive to histamine H2-receptor excitation in cells from dog gastric mucosa

A method of preparing viable cells from dog gastric mucosa is described. Cyclic AMP in these cells is elevated by histamine and 4-methyl histamine but 2-methyl histamine is only a weak agonist. The effects on cyclic AMP levels are inhibited competitively by metiamide and burimamide which give apparent K_Bvalues of 3.5×10^–7 M and 2.3×10^–6 M, respectively. These values are similar to those reported for other histamine H₂-receptor systems. The H₁-receptor antagonists, mepyramine and chlorpheniramine, have no inhibitory effect on the histamine induced elevation of cyclic AMP: promethazine inhibits the system but not by a competitive mechanism. It is concluded that the histamine stimulated adenylate cyclase system is probably located in the parietal cell component.     

Histamine-stimulated production of matrix metalloproteinase 1 by human rheumatoid synovial fibroblasts is mediated by histamine H1-receptors

The purpose of this study was to investigate the role of histamine in human rheumatoid synovial fibroblasts in the production of factors responsible for tissue remodelling and cartilage breakdown in rheumatoid arthritis. We examined the effects of histamine of tritiated thymidine incorporation, production of matrix metalloproteinase-1 (MMP-1), histamine H₁-receptor expression, phosphoinositide metabolism and intracellular calcium ion concentration ([Ca²⁺] _i ) in human rheumatoid synovial fibroblasts. Tritiated thymidine incorporation studies demonstrated that histamine markedly stimulated the proliferation of rheumatoid synovial fibroblasts. Immunofluorescence and Northern blot analyses revealed that proMMP-1 production was also stimulated by histamine. The levels of inositol phosphates and [Ca²⁺] _i in the cells were elevated in response to histamine, indicating that the cells expressed histamine H₁-receptors; and Northern blot analysis indicated that these H₁-receptors were up-regulated by histamine. In in situ hybridization, large amounts of histamine H₁-receptor mRNA were also detected in rheumatoid synovial tissue. These results suggest that the interaction between H₁-receptor expression in rheumatoid synovial fibroblasts and histamine secretion by mast cells and macrophages in the affected sites is an important event responsible for tissue remodelling and joint destruction in rheumatoid arthritis.     

Dual effect of antihistamines on rat peritoneal mast cells: Induction and inhibition of histamine release

A variety of H₁- and H₂-receptor agonists and antagonists are shown to have a dual effect on isolated rat peritoneal mast cells. At high concentrations the drugs induce histamine release while at low concentrations they inhibit the secretion of the amine evoked by antigen. These effects do not appear to be directly related. The ability of the H₁-antagonists to inhibit histamine release does not appear to correlate in simple fashion with their recorded pA₂ values as measured on the guinea pig ileum, suggesting that the effect is not mediated through H₁-receptors. These results are discussed in terms of the clinical utility of antihistaminic drugs.