Effect of lipopolysaccharides on histamine synthesis by hematopoietic cells.

We show herein that lipopolysaccharides (LPS), in vitro, synergize with GM-CSF to increase histamine synthesis by murine bone marrow cells. LPS has no effect on its own and does not potentiate histamine synthesis promoted by IL-3, the only other cytokine sharing this biological activity with GM-CSF. Despite the fact that GM-CSF and LPS synergistically increase PGE2 levels, the potentiating effect of LPS does not require PGE2 that have been previously shown to enhance GM-CSF-induced histamine synthesis. We provide evidence that this effect of LPS on histamine production by bone marrow cells is mediated by the intracellular cAMP transduction signal. In addition, LPS and cAMP enhance GM-CSF-induced histidine decarboxylase activity, showing that both substances act on histamine synthesis. Contrary to in vitro results, LPS injection into mice induces an increase in both intracellular histamine and HDC activity in bone marrow cells. Our results support the conclusion that this effect is mediated by GM-CSF. In conclusion, LPS appears to be a powerful HDC inducer in hematopoietic organs because of its ability, on one hand, to induce circulating GM-CSF and, on the other hand, to potentiate GM-CSF induction of HDC.     

Effects of histamine and cimetidine on the levels of serotonin and 5-hydroxyindoleacetic acid in various parts of the digestive tract and in the blood and brain of rats

In the investigations on male Wistar rats it was demonstrated that histamine (0.05 and 0.5 mg/kg) decreased the serotonin level, without affecting the level of 5-HIAA in the stomach and duodenum. Contrary to this, cimetidine (15, 75 and 150 mg/kg) raised slightly the level of serotonin and decreased the 5-HIAA level in the stomach and duodenum. In the jejunum histamine in the lower dose raised the levels of serotonin and 5-HIAA, and in the higher dose it decreased only the concentration of serotonin. Cimetidine, on the other hand, only in the highest dose increased the serotonin level and decreased significantly the level of 5-HIAA. In the brain a rise of the serotonin level was observed only after histamine. No effects were observed of histamine and cimetidine on the blood serotonin level. Histamine reduced the number of enterochromaffinocytes in the duodenum. These results point to an evident interaction between the histaminergic and the serotoninergic structures in the digestive tract of rats.     

Mouse mammary epithelial histamine system.

Histamine is suggested to play a role in mammary gland growth regulation, differentiation and functioning during pregnancy and lactation. Two pools of histamine are thought to be involved in these processes: mastocyte- and epithelial cell related histamine. In the present study we focused on epithelial cells. Immunohistochemistry has shown that the epithelial cells positive for histamine and L-histidine decarboxylase (HDC), the primary enzyme regulating histamine biosynthesis, were mainly found in cells forming alveolar structures in the mammary gland. Cultured primary mouse mammary epithelial cells (MMEC) expressed strong HDC immunoreactivity, especially dividing cells and non-differentiated ones. Histidine decarboxylase activity undergoes significant changes during pregnancy and lactation. Pregnancy associated intensive growth of the mammary gland coincided with an increase and the first days of lactation with a decrease of HDC protein expression. Binding studies with mammary tissue membranes and epithelial cell membranes revealed the presence of H1 and H3 but not H2 receptors. Summarizing, our data have shown that mammary epithelial cells are capable of synthesizing and excreting histamine and they bear histamine receptors. These findings further substantiate the role of histamine in mammary gland physiology.     

Localization of histamine in uterine structures

By means of luminescent-histochemical method of Cross, Even, Rost histamine is revealed in all uterine structures. Visual and fluorometric data demonstrate uneven distribution of histamine in the organ's structures. A high content of histamine is specific for macrophages and mast cells, less high--in tegmental epithelium and endometrial glands. A low level of histamine have endometrial stroma, smooth myocytes, cells of the serous membrane and vessels. Basing on the literature data, concerning various sensitivity of the uterine tissues to estrogens and regarding effect of the estrogens upon histamine metabolism in the uterine and regarding interconnection of the histamine receptors in the uterus and the estrogens, a suggestion is made that various contents of histamine in the uterine structures depend on various amount of the histamine receptors in them and on different abilities of the uterine tissues to inactivate histamine. The ability of macrophages to accept free forms of bioamines, as it is described in the literature, evidently can be spread to the uterine macrophages, where a high content of histamine is revealed.     

Role of pain component in the organization of chemosensory taste reaction]

The investigation of algoinductor (histaminergic) and peptidergic relations in peripheral pain reaction of taste was performed by using of different histamine liberators (applied on tongue). By fluorescence-histochemical methods it was shown that histamine in the apical portion of papilla is derived from cells of taste buds and in the basal zone--from connective tissue cells (including mast cells). It was established in behavior trials on peptidergic system that consumption of taste solutions became changed. It was suggested that histaminergic structures together with SP-containing fibers ensure food controlling in oral cavity.     

Mast cell-lysosomal cationic protein interaction: effects of metabolic inhibitors and decay of activated cells on enhanced fluorescence of anilinonaphthalene sulfonate

It has been shown earlier that the interactions of the isolated rat peritoneal mast cells with cationic protein from rabbit neutrophil lysosomes (band 2 protein) can be studied using anilinonaphthalene sulfonate (ANS) as a fluorescent probe. In the present communication, binding of ANS dye to the mast cells interacting of histamine release by metabolic inhibitors was found to have no effect on enhancement of ANS fluorescence. On the other hand, inhibition of histamine release at high concentration of Ca2+ (14.4 mM) was accompanied by the decrease in enhance fluorescence. In the presence of 7.2 mM of Sr2+, the release of histamine was enhanced with small but significant increase in ANS fluorescence. The cells heated to 42 degrees C partially lost their capacity to release histamine without the loss of enhanced fluorescence. The mast cells interacting with B2 at 10 degrees C for various time intervals showed time-dependent loss in histamine releasing capacity with concomitant loss in enhanced fluorescence. These studies suggest that the enhancement of ANS fluorescence is associated with the early events of the cell membrane caused by interaction of B2 with the cells. The extracellular cations significantly influence this early event.     

Immunocytochemical colocalization of histamine, histidine decarboxylase, 5-hydroxytryptamine and tyrosine hydroxylase in the superior cervical ganglion of the rat

Summary The coexistence of histamine, histidine decarboxylase (the enzyme synthesizing histamine), 5-hydroxytryptamine and tyrosine hydroxylase (the rate-limiting enzyme in catecholamine synthesis), was studied in the rat superior cervical ganglion with the indirect immunofluorescence method. Possible colocalization was examined by staining consecutive sections with two different antibodies, or alternatively in the same section by eluting the first antibody with a mild solution containing potassium permanganate and sulphuric acid, and by staining the same section with another antibody. It was shown that tyrosine hydroxylase immunoreactivity was found both in large principal nerve cells and in small cells, which on the basis of their size and high nucleus—cytoplasm ratio corresponded to small intensely fluorescent (SIF) cells. Histamine, histidine decarboxylase and 5-hydroxytryptamine immunoreactivities were observed only in SIF cells. Those SIF cells which were immunoreactive for histamine, histidine decarboxylase or 5-hydroxytryptamine also contained tyrosine hydroxylase immunoreactivity. On the other hand, all tyrosine hydroxylase-immunoreactive SIF cells were also immunoreactive for histidine decarboxylase or 5-hydroxytryptamine. Some of the SIF cells, which were non-reactive for histamine, were immunoreactive for tyrosine hydroxylase.     

Comparative functional characterization of mouse bone marrow-derived mast cells and peritoneal mast cells in response to non-immunological stimuli

The cultured mouse mast cells that are dependent on spleen-derived factor for their proliferation and maintenance and have been shown to be similar to mucosal mast cells in terms of their T-cell dependence and histochemical staining characteristics. Mast cell heterogeneity has been confirmed by functional characterization of mouse bone marrow-derived mast cells (MBMMC) and mouse peritoneal mast cells (MPMCs). MPMCs released around 30% of histamine when stimulated with compound 48/80 whereas MBMMC were almost unresponsive to the same stimulus. Calcium Ionophore A23187 on the other hand, released histamine in dose-dependent manner from MBMMC. The study was undertaken to investigate the effect of antiallergic drug, disodium cromoglycate (DSCG), a synthetic cromone and quercetin, a plant-derived flavonoid on Ca ionophore A23187 induced histamine release from MBMMC. MBMMCs were almost unresponsive to DSCG whereas Ca Ionophore induced histamine release was blocked by Quercetin. The results indicate that response of mast cells at one anatomic site to a given stimulus does not necessarily predict the response of mast cells at a different anatomic location to the same stimulus. It shows functional heterogeneity within a single species. So, it cannot be assumed that antiallergic compounds stabilizing mast cells in one tissue site or organ will be equally efficacious against mast cells in other sites.     

Histamine distribution in the uterine structures of ovariectomized rats administered estradiol, histamine antagonists and an inhibitor of prostaglandin synthesis

In the experiments performed on ovariectomized rats, using luminescent-histochemical method for revealing histamine after Cross, Ewen and Rost, it has been demonstrated that estradiol facilitates increasing histamine content in the uterine structures, as well as its redistribution--histamine content increases in the glandular and tegmental epithelia, in stromal cells, smooth myocytes and it decreases in macrophages. These manifestations of estradiol action are absent after cymetidin and indometacin, but not tavegil administration. The first two inhibit the morphological effect of estradiol in the uterus, indometacin making it in a greater degree. It is supposed that estradiol action, concerning provision of the uterine structures with histamine, takes place together with prostaglandins participation and at hormonal activation of H2-receptors. Taking into account the literature data on stimulating influence of estradiol on macrophagal phagocytosis and secretion, a conclusion is made that decreasing content of histamine in macrophages at estrogenization results from histamine release by these cells; macrophages are potential sources of histamine in the uterus.     

The crystal structure of D7r4, a salivary biogenic amine-binding protein from the malaria mosquito Anopheles gambiae

The D7-related (D7r) proteins of the malaria vector Anopheles gambiae have been shown to bind the biogenic amines serotonin, norepinephrine, and histamine with high affinity. One member of the group (D7r1 or hamadarin) has also been shown to have an anticoagulant/antikinin activity. To understand the mechanistic details of its antihemostatic/anti-inflammatory effects, we have determined the crystal structure of one member of this group, D7r4, along with the structures of ligand complexes with serotonin, tryptamine, histamine, and norepinephrine. The D7 fold consists of an arrangement of eight alpha-helices stabilized by three disulfide bonds. The structure is similar to those of the arthropod odorant-binding proteins, a relationship that had been predicted based on sequence comparisons. Although odorant-binding proteins commonly have six alpha-helices, D7r4 has eight, resulting in significantly different positioning and structure of the ligand binding pocket. The pocket itself is lined by hydrophobic side chains along with polar and charged groups oriented to form hydrogen bonds with the aliphatic amino group and with groups on the aromatic portions of the ligands. These structures, along with accompanying mutagenesis studies, have allowed us to identify critical residues for biogenic amine binding and to predict which members of the large D7 protein family found in blood-feeding nematocerous Diptera will function as biogenic amine-binding proteins.     

Histamine-induced potentiation of cholinergic transmission in chick oesophagus (Gallus gallus)

1. The effects of histamine on cholinergic nerve transmission were investigated in the oesophagus of the chick (0-29 days old). 2. Histamine potentiated the contractile responses produced by vagal or transmural nerve stimulation and by the ganglionic stimulant (DMPP) with the increase of tonus of oesophagus. On the other hand, a selective H2 agonist, 4-methylhistamine, did not have any effect. 3. The sensitivity of oesophagus to ACh did not change in the presence of histamine (0.2-2 microM). 4. Mepyramine but not metiamide antagonized the contractile and potentiating effects of histamine. 5. From these findings, it is concluded that histamine preferentially acts on H1-receptors located in cholinergic neurones to facilitate cholinergic transmission in the chick oesophagus, potentiating the nerve-mediated contraction.     

Self-organizing maps and molecular similarity

Self-organizing maps generated by Kohonen neural networks provide a method for transforming multidimensional problems into lower dimensional problems. Here, a Kohonen network is used to generate two-dimensional representations of the electrostatic potential about the ring structures of histamine H2 agonists. Previous work by J. Gasteiger and X. Li (Angew. Chem. Int. Ed. Engl. 1994, 33, 643) has shown the usefulness of such a method for classifying molecules as muscarinic or nicotinic agonists. Here, the method is extended to rank histamine H2 agonists in order of biological activity.     

Presence of histamine H2-receptors on human gastric carcinoma cell line MKN-45 and their increase by retinoic acid treatment.

Histamine dose-dependently stimulated cyclic AMP production in human gastric carcinoma cell line MKN-45, and this effect was inhibited by cimetidine but not by pyrilamine. Moreover, not only histamine but also cimetidine displaced the specific binding of [3H]tiotidine to these cells, whereas pyrilamine had no effect. On the other hand, pretreatment of MKN-45 cells with retinoic acid (RA) significantly enhanced histamine-induced increase of cyclic AMP production, although the cyclic AMP response to either forskolin or NaF was not affected. Finally, RA treatment increased the number of histamine receptor without altering its affinity. Thus, it appears that histamine H2-receptors are present on MKN-45 cells, and that RA treatment enhances the action of histamine on these cells by increasing the number of H2-receptors.     

Histamine receptor 2-mediated growth-differentiation factor-15 expression is involved in histamine-induced melanogenesis

Vitiligo is a progressive depigmenting disorder. Histamine has been shown to induce melanogenesis via histamine receptor 2, suggesting the possibility of histamine as a repigmenting agent for the treatment of vitiligo. However, the role and signaling mechanism of histamine are still unclear in melanogenesis, especially in relation to growth-differentiation factor-15, which is a protein belonging to transforming growth factor beta and found to be overexpressed in metastatic or malignant melanoma. We found that histamine induces growth-differentiation factor-15 in melanoma cell lines such as SK-MEL-2, B16F10, and melan-a cells. Therefore, in the present study, the role of growth-differentiation factor-15 in histamine-induced melanogenesis was investigated using gene silencing or overexpression of growth-differentiation factor-15 and histamine related compounds such as histamine, amthamine, and cimetidine. Gene silencing of growth-differentiation factor-15 suppressed histamine-induced proliferation, melanin production, tyrosinase activity, and chemotactic migration of SK-MEL-2 cells. Histamine-induced expression of tyrosinase, tyrosinase-related protein 1, and tyrosinase-related protein 2 was also suppressed by growth-differentiation factor-15 gene silencing. On the other hand, overexpression of growth-differentiation factor-15 using a plasmid containing growth-differentiation factor-15 in SK-MEL-2 cells increased melanin production and chemotactic migration. Amthamine induced expression of growth-differentiation factor-15 in a time and concentration dependent manner. Amthamine-induced expression of growth-differentiation factor-15 was suppressed by cimetidine.Our results suggest that growth-differentiation factor-15 is a new player in histamine-induced melanogenesis, which can help researchers to extend the knowledge of the role of the transforming growth factor beta family in melanogenesis and in skin pigment disorders such as vitiligo.     

Influence of blood sampling conditions upon histamine concentrations in rat plasma: a study of a complex relationship with plasma epinephrine

The concentrations of histamine reported vary considerably from species to species. The present studies sought to determine if blood sampling techniques were at least in part responsible for this large variability. Since plasma catecholamines are influenced by the stress associated with blood sampling, these biogenic amines also were measured. Finally, we explored the possible existence of a relationship between plasma histamine and plasma catecholamine concentrations.The present study confirms that concentrations of histamine in rat plasma are particularly large and establishes that the manner (e.g. awake, anesthetized) and site (e.g. intravenous, decapitation) of blood removal influence the concentrations obtained. The lowest histamine values were seen in samples taken from blood vessels in anesthetized rats. Blood obtained after decapitation showed increasing concentrations of plasma histamine in sequentially obtained samples.An inverse relationship appeared to exist between plasma histamine and plasma catecholamines (predominantly epinephrine). An inhibitory role of epinephrine upon decapitation-associated histamine release was suggested by the observation that both adrenalectomy and catecholamine depletion (alpha-methyl-para-tyrosine) elevated histamine concentrations. Our studies with propranolol, as well as work by other investigators, establish an inhibitory role of β-receptor stimulation on the release of histamine. On the other hand, histamine injected into the perfused rat adrenal caused a marked release of adrenomedullary catecholamines.In summary our study suggests the presence of a complex interaction between catecholamines and histamine in the regulation of the release of the individual amines. Our findings point to the existence of a histamine-adrenal axis in which the release of histamine may facilitate the release of epinephrine which in turn may restrict further release of histamine.     

Histamine and GABA. Hydrogen bonds and permeation of vesicles

Spectroscopic studies on sodium di(2-ethylhexyl)-sulfosuccinate (AOT) inverted micelles, films of AOT and L-alpha-lysolecithin and on dihexadecyl phosphate vesicles show that histamine and gamma-aminobutyric acid (GABA) act differently on these membrane models. Histamine increases the permeability of the membrane to ions through interactions with its polar sites. GABA, on the other hand, prefers self-association to association with the membrane. If these two neurotransmitters are applied jointly, the result is a decrease in the permeating effect of histamine. Possible mechanisms for these processes are discussed.     

Effect of histamine on duration of phases of the respiration cycle

Histamine produced either a bronchodilation or a bronchoconstriction in rats. In a 0.01-1.0 mcg/ml concentration histamine augmented the contractions amplitude in electrical stimulation of the trachea, in a 10-100 mcg/ml concentration histamine enhances the muscle tone thus decreasing the induced contractions. The histamine effects seems to be connected with its prevailing influence on different structures of the airways depending on the concentration. Its high concentrations act directly on the smooth muscle whereas its lower concentration affects receptors signaling the functional modules of the metasympathetic nervous system within the intramural ganglia of the trachea.     

Enzymatic histamine catabolism in vertebrate ontogenesis. A comparative study

1. The synthesizing and degrading activities of histamine were determined in the liver and small intestine of developing guinea pig and chick embryos. 2. Though increasing with age, HDC values were always 2-3 orders of magnitude lower than those of degrading enzymes. 3. DAO activity on the other hand was 10-100 fold higher than HMT at all ages studied, suggesting a decisive role for oxidative deamination in control of tissue histamine levels. 4. Generally histamine levels were higher in tissues of developing guinea pig than chick embryo, however, in the laying hen intestine histamine concentration was approximately 5 times greater than in the adult guinea pig intestine.     

The action of agonists and antagonists at the histamine H1 receptor and receptor protection studies in guinea pig ileum

We have examined the ability of histamine and the competitive reversible antihistamines to protect the histamine H1 receptor against alkylation with the 2-haloalkylamines, phenoxybenzamine and SY-14. In isolated guinea pig ileum these irreversible antagonists produce a parallel shift in the dose-response curve to histamine with retention of the maximum response if they are used at concentrations less than about 10(-6)M. Treatment with these 2-haloalkylamines in the presence of a high concentration of histamine did not alter the blocking activity. Thus histamine appears to be unable to protect its own receptor against irreversible blockade. The competitive reversible antagonists, on the other hand, did provide effective protection against irreversible blockade. It is likely that the competitive reversible H1 receptor antagonists have at least some part of their attachment site in common with irreversible antagonists of the 2-haloalkylamine type, while the inability of histamine to provide self-protection suggests that its primary attachment site is different from that of the antagonists.     

Histamine in stress ulcer prophylaxis in rats.

BACKGROUND: Gastrin and its analogues increase the gastric acid secretion, but also enhance mucosal defense mechanisms. On the other hand, increased formation of histamine leading to an increase in gastric acid secretion is accompanied with gastroprotection and acceleration of gastric ulcer healing. AIM: Of this study was to examine the effect of histamine on stress induced gastric ulcers in rats. METHODS: Male Wistar rats were exposed to water immersion and restrain stress (WRS) for 3.5 h at 23 degrees C. Before WRS rats were pretreated with saline, histamine, ranitidine or omeprazole. RESULTS: WRS produces gastric lesions which were strongly reduced by ranitidine or omeprazole. Also treatment with histamine markedly reduced ulcer area evoked by WRS. Addition of histamine to ranitidine or omeprazole caused an additional reduction in ulcer area. Gastroprotective effect of histamine was accompanied with the increase in gastric blood flow (GBF). Administration of omeprazole or ranitidine alone was without significant effect on GBF. Histamine caused an slight decrease in gastric luminal pH, whereas ranitidine or omeprazole significantly increased gastric luminal pH. Plasma interleukin-1beta was significantly reduced after administration of omeprazole, ranitidine, or histamine, however, the effect of histamine was less pronounced. DNA synthesis was increased after administration of omeprazole, ranitidine or histamine when compared with WRS alone. Administration of histamine in combination with ranitidine or omeprazole caused an additional increase in DNA synthesis. CONCLUSIONS: Histamine exhibits protective effect and increases gastroprotective effect of ranitidine and omeprazole against stress-induced gastric lesions. This effect of histamine seems to be independent on gastric acid secretion but related to the increase in gastric blood flow and the reduction in activation of cytokine cascade.