thioperamide and Asthma

Histamine is detected in high concentrations in the airways during an allergic asthma response. In a murine model of allergic asthma, the histamine H4 receptor (H4R)-selective ligand JNJ 7777120 reduces asthma-like symptoms. A sole antagonistic function of JNJ 7777120 at the murine H4R has, however, been questioned in the literature. Therefore, in the present study, we aimed at analyzing the effects of JNJ 7777120 in comparison to that of the H3/4R-selective antagonist thioperamide. Experimental murine asthma was induced by sensitization and provocation of BALB/c mice with ovalbumine (OVA). JNJ 7777120, thioperamide, or JNJ 5207852, an H3R-selective antagonist which was used to dissect H3R- and H4R-mediated activities of thioperamide, were injected subcutaneously during sensitization and effects were analyzed after provocation. Pharmacokinetic analyses revealed shortest t1/2 values in both plasma and lung tissue and lowest maximal concentration in lung tissue for JNJ 7777120 in comparison to thioperamide and JNJ 5207852. Nevertheless, JNJ 7777120 reduced serum titers of allergen-specific (anti-OVA) IgE, inflammatory infiltrations in lung tissue, and eosinophilia in bronchoalveolar lavage fluid. In contrast, thioperamide reduced only eosinophilia in bronchoalveolar lavage fluid, while anti-OVA IgE concentrations and lung infiltrations remained unaffected. JNJ 5207852 had no effect on these parameters. JNJ 7777120 provides beneficial effects in experimental murine asthma, which, however, could only partially be mimicked by thioperamide, despite more favorable pharmacokinetics. Thus, whether these effects of JNJ 7777120 are entirely attributable to an antagonistic activity at the murine H4R or whether an agonistic activity is also involved has to be reconsidered.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cell Count; Disease Models, Animal; Eosinophilia; Female; Histamine H3 Antagonists; Immunoglobulin E; Indoles; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Piperazines; Piperidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4

To investigate the effect of selective H3 receptor agonist(R)-alpha-methylhistamine and antagonist thioperamide on the respiratory response in asthmatic guinea pigs respectively.. Anesthesized guinea pigs were prepared with a implanted intracerebroventricular (icv) cannula and instrumented for the measurement of respiratory rate (RR) and diaphragmatic electric activity (DA). Substance P-like immunoreactive (SP-LI) substances in lower respiratory tract were detected by immunohistochemical method. Brain histamine contents were measured by fluorometric determination.. (1) Intravenous injection of ovalbumin caused tachypnea and significant decrease in DA magnitude. At the same time, SP-LI substances increased in trachea, bronchus and lung. (2) Administration of selective H3 receptor agonist (R)-alpha-methylhistamine (5 microg) icv immediately after i.v. ovalbumin could significantly ameliorate the changes in RR and DA induced by ovalbumin. In accordance, SP-LI substances in lower respiratory tract markedly decreased at 5 min and 10 min after (R)-alpha-methylhistamine microinjection. (3) Icv thioperamide (20 microg) caused a significant increase in RR and a decrease in DA. (4) Brain histamine contents increased in hypothalamus and cortex during asthma. After microinjection of thioperamide (20 microg) icv significant increase of histamine contents in hypothalamus and cortex was observed.. Brain histamine H3 receptors may be related to asthmatic respiratory responses.

Topics: Animals; Asthma; Brain; Guinea Pigs; Histamine Agonists; Histamine H3 Antagonists; Lateral Ventricles; Male; Methylhistamines; Muscle Contraction; Piperidines; Receptors, Histamine H3; Substance P; Trachea

High levels of histamine can be found in the airways of asthma patients. This study describes the effects of histamine on anti-CD3-induced production of IL-4, IL-5, and IFN-gamma by T cell clones from subjects with allergic asthma and healthy subjects. T cell clones were obtained from bronchoalveolar lavage (BAL) fluid and blood. The number of clones tested, and the percentage of clones in which histamine inhibited or enhanced cytokine production by more than 25%, were as follows: IL-4, 47, 8.5%, and 4.3%; IL-5, 43, 14%, and 30%; and IFN-gamma, 52, 40%, and 15%. Inhibition of IL-5 and IFN-gamma production was reversed by IL-2. The enhancement of IFN-gamma production was associated with an enhancement of both IL-2 production and proliferation. In 21% of the clones a combined effect consisting of inhibition of IFN-gamma production and enhancement of IL-5 production was found. This response was reversed by H2-receptor antagonists and was significantly associated with a histamine-induced increase in intracellular levels of cAMP. The role of cAMP in mediating the histamine effects was supported by the observations that the beta2-agonist salbutamol had effects similar to histamine and that high concentrations of PGE2 mimicked the inhibitory effects of histamine. Clones from BAL fluid and blood showed similar responses, as did clones from patients with asthma and from control subjects. The enhancement of IFN-gamma production by histamine, however, was found only in clones from healthy subjects. The results warrant further investigations on the role of cAMP in the regulation of cytokine production.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Albuterol; Asthma; Bronchoalveolar Lavage Fluid; Clone Cells; Cyclic AMP; Dinoprostone; Enzyme Activation; Famotidine; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Impromidine; Interferon-gamma; Interleukin-2; Interleukin-4; Interleukin-5; Lung; Methylhistamines; Piperidines; Pyridines; Ranitidine; T-Lymphocytes; Triprolidine

Airway goblet cell hypersecretion may contribute to the pathophysiology of asthma. However, it is unknown whether histamine affects goblet cell secretion and, if so, which subtype of histamine receptor is involved and whether endogenous histamine-degrading enzymes modulate these actions.. We morphometrically assessed goblet cell secretion in the guinea pig trachea stained with alcian blue and periodic acid Schiff stains by measuring the mucus score, which was inversely related to the degree of mucus glycoprotein discharge.. Inhalation of histamine caused a dose-dependent decrease in mucus score, an effect that was inhibited by pretreatment with the H2-receptor antagonist cimetidine but not with the H1-receptor antagonist mepyramine or the H3-receptor antagonist thioperamide. Inhaled Dimaprit, a selective H2-receptor agonist, likewise decreased mucus score; whereas stimulation of H1- and H3-receptors with 2-methylhistamine and (R)-alpha-methylhistamine, respectively, had no effect. Pretreatment with the histamine N-methyltransferase inhibitor SKF 91488, but not the diamine oxidase inhibitor aminoguanidine, potentiated the dose-dependent effect of histamine on goblet cell secretion, causing a decrease in the concentration of inhaled histamine required to produce a half-maximal effect from 0.80 +/- 0.12 to 0.48 +/- 0.09 mg/ml (p < 0.01). The histamine methyltransferase activity in the tracheal mucosa was 29 times higher than diamine oxidase activity.. These findings suggest that histamine stimulates airway goblet cell secretion through H2-receptors and that this effect may be modulated principally by endogenous histamine methyltransferase through a degradation of histamine.

Topics: Amine Oxidase (Copper-Containing); Animals; Asthma; Cimetidine; Dimaprit; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glycoproteins; Guanidines; Guinea Pigs; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Histamine N-Methyltransferase; Male; Methylhistamines; Mucus; Piperidines; Pyrilamine; Recombinant Proteins; Trachea

There is increased recognition that lung mast cell mediators not only produce the symptoms of acute asthma, but also result in the recruitment and activation of additional proinflammatory cells, such as eosinophils. Histamine, one of the major mast cell mediators, is known to have numerous effects on eosinophil function. These effects of histamine are mediated by distinct receptors on the surface of eosinophils, only some of which have been characterized. Prior studies have suggested that eosinophils have non-H1, non-H2 histamine receptors which mediate the chemotactic effects of histamine. We observed previously that the histamine-induced increase in cytosolic calcium in human eosinophils could not be blocked by classic H1 or H2 antagonists, but could be inhibited by the H3 antagonist thioperamide. The purpose of this study was to further characterize the pharmacologic properties of this calcium-linked histamine receptor. Using Fura-2 loaded eosinophils to measure the concentration of cytosolic calcium, we examined the effect of additional histamine receptor antagonists and agonists. We found that the pKb for the H3 antagonists thioperamide, impromidine, and burimamide (8.1, 7.6, and 7.2, respectively), were similar to those reported for H3 receptors in the central nervous system, suggesting that the eosinophil histamine receptor was similar to H3 receptors. However, when the known H3 agonists were tested for activity ([R]-alpha-methylhistamine, N alpha-methylhistamine), the potencies of these compounds were much less than the potency of histamine itself, indicating a significant difference between H3 receptors and this eosinophil histamine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Anticonvulsants; Asthma; Burimamide; Calcium; Eosinophils; Fura-2; Histamine Agonists; Histamine Antagonists; Humans; Impromidine; Inflammation; Intracellular Fluid; Mast Cells; Methylhistamines; Phosphatidylethanolamines; Piperidines; Platelet Aggregation Inhibitors; Receptors, Histamine