Lack of association between atopic asthma and polymorphisms of the histamine H1 receptor, histamine H2 receptor, and histamine N-methyltransferase genes.
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Asthma↗
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A technique for the flow cytometric analysis of lymphocytes bearing histamine receptors.
Histamine receptors have been demonstrated on lymphocyte membranes by a variety of techniques. We now report a method that allows for the flow cytometric analysis of histamine receptors on human peripheral T cells. Histamine is conjugated to fluoresceinated human albumin by the coupling agent ECDI. This conjugated histamine compound (FHA-his) binds to approximately 45% of T cells. Fluoresceinated human albumin alone (FHA), not conjugated to histamine, does not bind to T cells. In addition, unconjugated histamine can inhibit completely the binding seen with FHA-his. We conclude that this technique demonstrates specific FHA-his binding to histamine receptors on T cells and can be used to determine the number of cells bearing such receptors. In addition, the reagent could be used with a cell sorter to isolate distinct histamine-receptor-bearing (HR+) cells for further immunologic study.
Blood Cell Count↗
Development of a homogeneous binding assay for histamine receptors.
Histamine is critically involved in a wide range of physiological and pathological processes through its actions at different receptors. Thus, histamine receptors have been actively pursued as therapeutic targets in the pharmaceutical industry for the treatment of a variety of diseases. There are currently four histamine receptors that have been cloned, all of which are G protein-coupled receptors. Studies from both academia and pharmaceutical companies have identified compounds that modulate the function of specific histamine receptors. These efforts led to the successful introduction of histamine H(1) and H(2) receptor antagonists for the treatment of allergy and excess gastric acid secretion, respectively. Histamine H(3) receptor ligands are currently under investigation for the treatment of obesity and neurological disorders. The recently identified histamine H(4) receptor is preferentially expressed in the immune tissues, suggesting a potential role in normal immune functions and possibly in the pathogenesis of inflammatory diseases. Even with the long history of histamine research and the important applications of histamine receptor ligands, assays to measure the affinity of compounds binding to histamine receptors are still routinely analyzed using a filtration assay, a very low-throughput assay involving washing and filtration steps. This article describes a simple, robust, and homogeneous binding assay based on the scintillation proximity assay (SPA) technology that provides results equivalent to those obtained using the more complex filtration assay. The SPA format is easily adapted to high-throughput screening because it is amenable to automation. In summary, this technique allows high-throughput screening of compounds against multiple histamine receptors and, thus, facilitates drug discovery efforts.
Animals↗
Cardiac histamine receptors.
Histamine can produce inotropic and chronotropic responses in both guinea pig and rabbit heart. In the guinea pig the responses are mediated primarily through stimulation of H2 receptors with H1 receptors being found mainly in left atria. In the rabbit H1 receptors predominate; H2 receptors are found only in right atria and are partially responsible for the chronotropic effect. H2 receptors are always associated with cyclic AMP, whereas H1 receptors are not. H2-histamine receptors and beta-adrenergic receptors have a number of properties in common. Stimulation of either receptor results in positive inotropic and chronotropic effects and increases in cyclic AMP and phosphorylase a. H2 and beta-adrenergic agonists will also both restore the action potential in K+-depolarized cardiac muscle. H1 and alpha-agonists, on the other hand, will also produce an inotropic effect. The effect is not dependent on cyclic AMP and can only be demonstrated under certain conditions. Neither agonist will restore the action potential in depolarized cardiac tissue. It is concluded that, although H2 and beta-agonists and H1 and alpha-agonists may have a common mechanism of action, the two groups of drugs (H2, beta versus H1, alpha) differ from each other with regard to mechanism.
Animals↗
Cloning and characterization of a novel human histamine receptor.
Histamine exerts its numerous physiological functions through interaction with G protein-coupled receptors. Three such receptors have been defined at both the pharmacological and molecular level, while pharmacological evidence hints at the existence of further subtypes. We report here the cloning and characterization of a fourth histamine receptor subtype. Initially discovered in an expressed-sequence tag database, the full coding sequence (SP9144) was subsequently identified in chromosome 18 genomic sequence. This virtual coding sequence exhibited highest homology to the H(3) histamine receptor and was used to generate a full-length clone by polymerase chain reaction (PCR). The distribution of mRNA encoding SP9144 was restricted to cells of the immune system as determined by quantitative PCR. HEK-293 cells transiently transfected with SP9144 and a chimeric G protein alpha-subunit (Galpha(q/i1,2)) exhibited increases in intracellular [Ca(2+)] in response to histamine but not other biogenic amines. SP9144-transfected cells exhibited saturable, specific, high-affinity binding of [(3)H]histamine, which was potently inhibited by H(3) receptor-selective compounds. The rank order and potency of these compounds at SP9144 differed from the rank order at the H(3) receptor. Although SP9144 apparently coupled to Galpha(i), HEK-293 cells stably transfected with SP9144 did not exhibit histamine-mediated inhibition of forskolin-stimulated cAMP levels. However, both [(35)S]GTPgammaS binding and phosphorylation of mitogen-activated protein kinase were stimulated by histamine via SP9144 activation. In both of these assays, SP9144 exhibited evidence of constitutive activation. Taken together, these data demonstrate that SP9144 is a unique, fourth histamine receptor subtype.
Amino Acid Sequence↗
Increase of human platelet serotonin uptake by atypical histamine receptors.
Histamine and the guanosine 3',5'-cyclic monophosphate (cGMP)-inducing agent sodium nitroprusside both increased serotonin (5-HT) uptake and cGMP levels in isolated human platelets in vitro. Histaminergic stimulation was observed at concentrations ranging from 10 nM to 0.25 microM [mean effective concentration (EC50) = 0.1 microM histamine]. The inhibition produced by the H2-receptor antagonists tiotidine, metiamide, and cimetidine was 10-10(5) times more potent on histamine receptors regulating 5-HT uptake and cGMP generation in human platelets than on the histaminergic receptors H1, HIC, H2, and H3 in other tissues. The in vitro histamine-induced 5-HT uptake was prevented by preincubation of isolated human platelets in the presence of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine or the cGMP-lowering agent LY-83583. Histamine was ineffective in stimulating cAMP generation in human platelets and did not interact with effector sites known to downregulate 5-HT uptake, including imipramine, gamma-aminobutyric acid A, peripheral type benzodiazepine-binding sites, and V1a vasopressin receptors inducing human platelet shape change and aggregation. These atypical human platelet histaminergic receptors differ from the previously classified histamine receptors by their apparent high affinity to histamine H2-receptor antagonists and their apparent link with the soluble, nitric oxide-dependent guanylate cyclase. These findings suggest that human platelets express a new subtype H2h of histamine receptors.
Adult↗
[The H1 and H2 histamine receptors].
Histamine is a major mediator of the allergic reactions. Histamine have different actions: contraction of smooth muscles, vascular action, increase in gastric and adrenal medulla secretion. Effects on central or peripheral nervous system are discussed. The specific H1 or H2 activity explains the different configurations of histamine. The specificity of H1 receptors agonists is now well known: H1 activities have a positive charge on the side chain with an imidazole ring able to rotate around the axis of side chain. The contraction of smooth muscles is due to the action of H1 receptors agonists. Many doubts remain about the exact structures of the H2 receptors, and their agonists. Trough the H2 receptors occur dilatation of small arteries and capillaries, as well as an increase in gastric secretion. Subdivisions of H2 receptors have been, suggested. Recently H3 receptors have been described in the brain and in some peripheral tissues. Interrelations between H1 and H2 histamine receptors have been described as well as a feedback of synthesis and of histamine release.
Animals↗
Chick retinal pigment epithelium. A new culture system for studying H2-histamine receptors.
Histamine elevates the intracellular cyclic AMP levels in cultured embryonic chick retinal pigment epithelium. The half-maximal activity is 6 X 10(-6) M. The effect of histamine is mediated by H2 receptors, i.e., inhibited by the H2 antagonist cimetidine and not affected by the H1 antagonists diphenhydramine and pyrilamine. The inhibition constant (KI) of cimetidine is 1.3 X 10(-8) M. Thus, the present system offers the opportunity of studying the nature of coupling between histamine receptors and adenylate cyclase under controlled conditions in a homogeneous cell type.
Animals↗
[Regulation of gastric juice secretion by gastric wall cell receptors--histamine H2 receptors, muscarine- and gastrin receptors].
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Animals↗
Selective effect of levocabastine on histamine receptor and histamine release from human leukocytes and guinea pig isolated tissue.
BACKGROUND: Levocabastine is a potent histamine H1 receptor antagonist used topically in the treatment of patients with allergic rhinitis. It has been suggested that antihistamines also have anti-inflammatory properties. OBJECTIVE: The present study was performed to investigate whether levocabastine, in addition to the anti-H1 receptor activity, has anti-inflammatory properties and thus is able to modulate the release of histamine and cytokines, such as interleukin 5 from human leukocytes and isolated tissues. METHODS: Leukocytes suspensions were prepared by dextran sedimentation of peripheral venous blood drawn from allergic and healthy volunteers. Leukocytes obtained from allergic volunteers were preincubated for 30 minutes with levocabastine (doses 10(-8) M to 10(-6) M) and thereafter incubated with allergen. Leukocytes obtained from healthy volunteers were incubated for zero to three hours with levocabastine (doses 10(-14) M to 10(-3) M). Histamine release was measured by an automated fluorometric method. Interleukin-5 release was measured by enzyme linked immunoassay. Contractile responses to histamine on guinea pig trachea and lung parenchyma as well as the release of histamine and interleukin-5 by the tissues were investigated in the absence or presence of levocabastine and/or the histamine H2 receptor antagonist cimetidine. RESULTS: Levocabastine did not influence allergen-induced histamine release from leukocytes obtained from allergic volunteers. High concentrations (10(-4)and 10(-3) M) of levocabastine, however, caused release of histamine from leukocytes obtained from healthy volunteers as well as guinea pig airway smooth muscle tissues. Pretreatment with levocabastine dose-dependently decreased the contractile response to histamine, showing an irreversible competitive mechanism. Interleukin 5 release from human leukocytes and by guinea pig airway smooth muscle was not detectable. CONCLUSIONS: These findings indicate that the H1 receptor blocker, levocabastine, has probably no anti-inflammatory properties, measured as histamine release, and that the histamine release from both human leukocytes and guinea pig trachea and lung parenchyma is significantly increased by the drug only at high concentrations.
Adult↗
Interaction of imidazoline alpha-adrenergic receptor antagonists with histamine receptors.
Because the alpha-adrenergic receptor antagonists phentolamine and tolazoline are similar in structure to histamine, it is possible that the vasodilatation caused by these drugs may be due in part to stimulation of histamine receptors. The vascular effects of these agents were studied in the hindquarters of rats and the gracilis muscle of dogs. To eliminate interruption of sympathetic vasoconstrictor tone as a mechanism of vasodilatation, all animals were treated with the alpha-adrenergic receptor antagonist, dibozane. After dibozane, histamine caused vasodilatation in the rat, whereas both tolazoline and phentolamine caused vasoconstriction. It is concluded that phentolamine and tolazoline do not stimulate vascular histamine receptors in the rat. In the dog, after alpha-receptor blockade, phentolamine and tolazoline caused vasodilatation, as did histamine. Responses to histamine were partially attenuated by mepyramine and greatly attenuated by the combination of mepyramine and metiamide, indicating the participation of both H1- and H2-histamine receptors. Vasodilatation caused by phentolamine was not reduced by antihistamines and does not appear to involve histamine receptors. Vasodilatation following tolazoline was blocked by metiamide but not mepyramine. It is concluded that in addition to blockade of alpha-adrenergic receptors, tolazoline can cause vasodilatation by stimulation of histamine H2-receptors.
Adrenergic alpha-Antagonists↗
Competitive blockade of adrenergic alpha-receptors and histamine receptors by thymoxamine.
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Animals↗
Ascorbate enhancement of H1 histamine receptor sensitivity coincides with ascorbate oxidation inhibition by histamine receptors.
Ascorbate has previously been shown to enhance both alpha(1)- and beta(2)-adrenergic activity. This activity is mediated by ascorbate binding to the extracellular domain of the adrenergic receptor, which also decreases the oxidation rate of ascorbate. H1 histamine receptors have extracellular agonist or ascorbate binding sites with strong similarities to alpha(1-) and beta(2)-adrenergic receptors. Physiological concentrations of ascorbate (50 microM) significantly enhanced histamine contractions of rabbit aorta on the lower half of the histamine dose-response curve, increasing contractions of 0.1, 0.2, and 0.3 microM histamine by two- to threefold. Increases in ascorbate concentration significantly enhanced 0.2 microM histamine (5-500 microM ascorbate) and 0.3 microM histamine (15-500 microM ascorbate) in a dose-dependent manner. Histamine does not measurably oxidize over 20 h in oxygenated PSS at 37 degrees C. Thus the ascorbate enhancement is independent of ascorbate's antioxidant effects. Ascorbate in solution oxidizes rapidly. Transfected histamine receptor membrane suspension with protein concentration at >3.1 microg/ml (56 nM maximum histamine receptor) decreases the oxidation rate of 392 microM ascorbate, and virtually no ascorbate oxidation occurs at >0.0004 mol histamine receptor/mol ascorbate. Histamine receptor membrane had an initial ascorbate oxidation inhibition rate of 0.094 min.microg protein(-1).ml(-1), compared with rates for transfected ANG II membrane (0.055 min.microg protein(-1).ml(-1)), untransfected membrane (0.052 min.microg protein(-1).ml(-1)), creatine kinase (0.0082 min.microg protein(-1).ml(-1)), keyhole limpet hemocyanin (0.00092 min.microg protein(-1).ml(-1)), and osmotically lysed aortic rings (0.00057 min.microg wet weight(-1).ml(-1)). Ascorbate enhancement of seven-transmembrane-spanning membrane receptor activity occurs in both adrenergic and histaminergic receptors. These receptors may play a significant role in maintaining extracellular ascorbate in a reduced state.
Amino Acid Sequence↗
Epidermal growth factor receptor - but not histamine receptor - is upregulated in seasonal allergic rhinitis.
BACKGROUND: We were interested in exploring the molecular mechanisms underlying the observed difference in histamine (H) responsiveness between seasonal allergic rhinitic (SAR) and nonrhinitic (NR) subjects. We hypothesized that SAR subjects express higher nasal mucosal histamine receptor 1 (H1R) and 2 (H2R) levels than do NR subjects. In addition, we examined expression of genes involved in regulating the glandular response, including epidermal growth factor (EGF), EGF receptor (EGFR), and mucins (Muc5Ac and Muc5B). METHODS: Fourteen subjects, seven SAR and seven NR, were provoked during pollen season with doubling doses of H (0.125-8.0 mg/ml). Nasal airway resistance (NAR) was measured by active posterior rhinomanometry. Provocation was halted when NAR exceeded 150% of baseline. Prior to provocation, nasal scrapings were obtained and mRNA quantified using two-step real-time PCR. RESULTS: The mean PD50 (concentration of H producing a 50% increase in NAR) was significantly lower in the SAR than NR group (0.36 vs 1.32 mg/ml; P < 0.05). The ratio of relative gene copy numbers between the SAR and NR groups were as follows: H1R, 0.85 (P = 0.52); H2R, 0.67 (P = 0.35); EGF, 1.02 (P = 0.93), and EGFR, 103.5 (P < 0.05). CONCLUSIONS: There were no significant differences in H1R or H2R mRNA levels between SAR and NR subjects in-season, despite observed differences in H reactivity. SAR subjects, however, did show a significant elevation in EGFR expression, consistent with the observation of mucus hypersecretion in allergic rhinitis.
Adult↗
Expression of histamine receptors and effect of histamine in the rat carotid body chemoafferent pathway.
Chemosensory information from peripheral arterial oxygen sensors in the carotid body is relayed by petrosal ganglion neurons to the respiratory networks in the medulla oblongata. Biogenic amines, including histamine, released from glomus (type I) cells of the carotid body are considered to be primary transmitters in hypoxic chemosensitivity. Immunocytochemistry at light-and electron-microscopical levels, and RT-PCR, revealed the expression of histamine receptors 1 and 3 as well as histidine decarboxylase in the rat carotid body glomus cells and petrosal ganglion neurons. Histamine receptors 1 and 3, but not histidine decarboxylase, were also observed in the ventrolateral, intermediate and commissural subnuclei of the nucleus tractus solitarii in the medulla oblongata. In order to examine the possible role of histamine in the afferent branch of the respiratory system, we applied histamine receptor 1 and 3 agonists to the carotid body, which caused a mildly increased phrenic nerve activity in a working heart-brainstem preparation. Moreover, microinjection of antagonists of histamine receptors 1 and 3 into the nucleus tractus solitarii caused significant changes in the inspiratory timing and the chemoreceptor response. Our data show that histamine acting via histamine receptors 1 and 3 plays an important neuromodulatory role in the afferent control of chemosensitivity.
Afferent Pathways↗
[Histamine receptors in the female reproductive system. Part II. The role of histamine in the placenta, histamine receptors and the uterus contractility].
The presence of the mast cells was confirmed not only in the uterus but also in the placental tissue. Mediators released from the placental mast cells may play a role in regulation of placental blood flow and normal blood pressure. Processes such uptake and clearance of vasoactive mediators may be upset in those women who developed pre-eclampsia. Histamine released from the placental mast cells may be involved in the mechanisms controlling myometrium contractility during the labour at term and preterm delivery. There is a correlation between the level of placental histamine and presence (or not) uterus contractility. Histamine produce a contractile response in isolated myometrial strips, in the majority of mammals, via H1 histamine receptors activation, but in some species e.g. rat, predominant response of uterus is relaxation (via H2 histamine receptors activation). Predominant response of the human uterus to histamine is contraction. Relaxation of human myometrial strips may be evoked after earlier usage of H1 receptors antagonists, although some H2 receptors agonists (e.g. dimaprit) induce the relaxation of human uterus without H1 receptors antagonists. Myometrium contractile activity is under control of sexual hormones. Neither the presence of H3 histamine receptors on the human myometrial smooth cells nor its role in the female reproductive system regulation was proved. Lack of the functional H3 receptors either on the smooth muscle cells or neuronal components of the animals' myometrium was shown in some studies.
Animals↗
[Effect of activation of alpha- and beta-adrenergic receptors, M-cholinergic receptors and H1-histamine receptors on mechanical tension in the frog subclavian vein].
The effects of adrenaline, noradrenaline, isoproterenol, dopamine, histamine, acetylcholine, and serotonin on the wall tension in the isolated frog subclavian vein and modification of these effects by appropriate antagonists were examined. The existence of alpha- and beta-adreno-, M-choline- and H1-histamine receptors was demonstrated. Stimulation of alpha-adreno- and H1-histamine receptors augments and that of beta-adreno- and M-cholinoreceptors diminishes active wall tension in the vein.
Adrenergic Agonists↗
Histamine-receptor bearing lymphocytes. II. The use of flow cytofluorometric analysis of histamine-receptors on mouse lymphocytes of different organs.
The histamine binding capacity of cells in various lymphoid organs has been determined by flow cytofluorometric (FCF) analysis of histamine receptors. Using fluoresceinated bovine serum albumin conjugated to histamine (HIS-BSA-FITC) as a staining reagent two distinct lymphocyte subpopulations of differing fluorescence intensity have been identified in each organ investigated. The thymus has a low number of histamine-receptor bearing cells, while bone marrow, lymph nodes and spleen reveal increasing binding capacities to the histamine conjugate. It is suggested that there exists a different susceptibility of distinct lymphocyte subpopulations for histamine, thereby enabling its controlled immunoregulatory activity.
Animals↗