Endothelium-dependent relaxation of rat aorta to a histamine H3 agonist is reduced by inhibitors of nitric oxide synthase, guanylate cyclase and Na+,K+-ATPase

The possible involvement of different effector systems (nitric oxide synthase, guanylate cyclase, β-adrenergic and muscarinic cholinergic receptors, cyclooxygenase and lipoxygenase, and Na+,K+-ATPase) was evaluated in a histamine H3 receptor agonist-induced ((R)α-methylhistamine, (R)α-MeHA) endothelium-dependent rat aorta relaxation assay. (R)α-MeHA (0.1 nM – 0.01 mM) relaxed endothelium-dependent rat aorta, with a pD2 value of 8.22 ± 0.06, compared with a pD2 value of 7.98 ± 0.02 caused by histamine (50% and 70% relaxation, respectively). The effect of (R)α-MeHA (0.1 nM – 0.01 mM) was competitively antagonized by thioperamide (1, 10 and 30 nM) (pA2 = 9.21 ± 0.40; slope = 1.03 ± 0.35) but it was unaffected by pyrilamine (100 nM), cimetidine (1 μM), atropine (10 μM), propranolol (1 μM), indomethacin (10 μM) or nordthydroguaiaretic acid (0.1 mM). Inhibitors of nitric oxide synthase, L-NG-monomethylarginine (L-NMMA, 10 μM) and NG-nitro-L-arginine methylester (L-NOARG, 10 μM) inhibited the relaxation effect of (R)α-MeHA, by approximately 52% and 70%, respectively). This inhibitory effect of L-NMMA was partially reversed by L-arginine (10 μM). Methylene blue (10 μM) and ouabain (10 μM) inhibited relaxation (R)α-MeHA-induced by approximately 50% and 90%, respectively. The products of cyclooxygenase and lipoxygenase are not involved in (R)α-MeHA-induced endothelium-dependent rat aorta relaxation nor are the muscarinic cholinergic and β-adrenergic receptors. The results also suggest the involvement of NO synthase, guanylate cyclase and Na+,K+-ATPase in (R)α-MeHA-induced endothelium-dependent rat aorta relaxation

Defining the role of mast cells in guinea pig models of asthma

Asthma is a common respiratory disease characterized by several pathophysiological features, such as allergen induced bronchoconstriction (in allergic asthma), airway hyperresponsiveness (AHR), airway inflammation, airway remodeling and mast cell hyperplasia. An increase of mast cells has been found in asthma patients. However, how these cells are involved in the development of asthma are not well defined. To investigate the role of mast cells in the pathophysiological characteristics of asthma, we established asthma models in guinea pigs, which have many similarities with humans, by exposing the animals to human relevant allergens: house dust mite (HDM) and cat dander extract (CDE). The involvement of mast cells in asthma-like features was investigated either by the addition of mast cell mediator antagonists or inhibitors, or inducing mast cell death. In paper I, we repeatedly exposed guinea pigs to HDM via intranasal instillation for seven weeks and successfully recaptured the antigen induced bronchoconstriction, the production of HDM specific immunoglobulins, AHR, eosinophilic inflammation with an increase of IL-13, airway remodeling (e.g., subepithelial collagen deposition and goblet cell hyperplasia) and mast cell hyperplasia. This model can be further used to study the role of mast cells in asthma. In paper II, we exposed guinea pigs to HDM or CDE intranasally for different time. Both HDM and CDE induce airway inflammation and airway remodeling after 4 weeks’ antigen exposures. These increases maintained after 8- and 12-week exposures. Exposing to both antigens for 8 weeks and 12 weeks induced a clear expansion of mast cells which is predominated by mast cells expressing tryptase. An increase of mast cells expressing both tryptase and chymase were also observed. In paper III, we isolated guinea pig trachea for comparing the effect of different mast cell agonists (HDM and Compound 48/80 (C48/80)) on airway smooth muscle responses and mediator release. We found that histamine, prostaglandins and 5- lipoxygenase products mediated the bronchoconstriction induced by HDM and C48/80. Both agonists induced a release of histamine, prostaglandin D2 and leukotriene B4. However, distinct of lipid mediator profiles were observed. The leukotriene E4 was only elevated by HDM, whereas C48/80 induced a broader release of lipid mediators. In paper IV and V, we identified an antibiotic monensin that can induce mast cell death. To examine if monensin can be a tool for investigating the role of mast cells in asthma, we cultured guinea pig tracheal segments from HDM sensitized guinea pigs and human bronchi with different concentrations of monensin for different time. We found that monensin has robust effects on causing mast cell death and totally blocked the HDM (in guinea pig trachea) and anti-IgE (in human bronchi) induced bronchoconstriction after 2 to 72h exposure without affecting the general tissue viability at low concentration. In the in vivo investigations, we exposed the guinea pigs to HDM repeatedly with or without monensin interventions. Monensin reduced the AHR, airway inflammation and mast cell hyperplasia in the HDM induced guinea pig model. In conclusion, exposing to human relevant allergens (HDM and CDE) are suitable for modeling of allergic asthma in guinea pigs. The increase of mast cells by HDM and CDE helps to investigate the role of mast cells in asthma models. Mast cells in guinea pig airways can respond differently to antigen and non-antigen agonists. Monensin can be a robust tool to induce mast cell death. The antigen induced bronchoconstriction by HDM in guinea pig trachea and anti-IgE in human bronchi are purely mast cell mediated. Our findings emphasize that mast cells have important roles in the development of AHR and airway inflammation in the guinea pig model used in this PhD study. The findings in this thesis highlight the importance of mast cells in asthma and the models we developed can be used as important tools for defining the mechanisms behind asthma

Signaling and regulation of G protein-coupled receptors in airway smooth muscle

Signaling through G protein-coupled receptors (GPCRs) mediates numerous airway smooth muscle (ASM) functions including contraction, growth, and "synthetic" functions that orchestrate airway inflammation and promote remodeling of airway architecture. In this review we provide a comprehensive overview of the GPCRs that have been identified in ASM cells, and discuss the extent to which signaling via these GPCRs has been characterized and linked to distinct ASM functions. In addition, we examine the role of GPCR signaling and its regulation in asthma and asthma treatment, and suggest an integrative model whereby an imbalance of GPCR-derived signals in ASM cells contributes to the asthmatic state

Histamine increases neuronal excitability and sensitivity of the lateral vestibular nucleus and promotes motor behaviors via HCN channel coupled to H2 receptor

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Rodent models of complement activation-related pseudoallergy: Inducers, symptoms, inhibitors and reaction mechanisms

Complement activation-related pseudoallergy (CARPA) is a hypersensitivity reaction to intravenous administration of nanoparticle-containing medicines (nanomedicines). This review focuses on CARPA in rodent models: rats, mice, guinea pigs and rabbits. Information on all aspects of hypersensitivity reactions caused by known complement activators (zymosan, cobra venom factor) and different nanomedicines (liposomes, other drug carrier nanocarriers) in these species has been compiled and analyzed, trying to highlight the similarities and differences. What is most common in all species' reactions to i.v. complement activators, liposomes and other nanoparticles is a dose-dependent hemodynamic and cardiopulmonary disturbance manifested in acute, reversible rise or fall of blood pressure and respiratory distress that can lead to shock. Other symptoms include heart rate changes, leukopenia followed by leukocytosis, thrombocytopenia, hemoconcentration due to fluid extravasation (rise of hematocrit) and rise of plasma thromboxane B2. The results of a recent rat study are detailed, which show that rats are 2-3 orders of magnitude less sensitive to liposome-induced CARPA than pigs or hypersensitive humans. It is concluded that CARPA can be studied in rodent models, but they do not necessarily mimic the human reactions in terms of symptom spectrum and sensitivity. © 2015 by De Gruyter

The role of histamine in neurogenic inflammation

The term ‘neurogenic inflammation’ has been adopted to describe the local release of inflammatory mediators, such as substance P and calcitonin gene-related peptide, from neurons. Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene-related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established. The aim of this review is to summarize the most recent findings on the role of histamine in neurogenic inflammation, with particular regard to nociceptive pain, as well as neurogenic inflammation in the skin, airways and bladder. LINKED ARTICLES: This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-