Antigen-induced Histamine Release Research Articles

Association between exposure to potassium aluminum tetrafluoride and bronchial hyperractivity and asthma

There is a possibility of a yet undescribed mechanism that might be involved in the development of occupational asthma in workers exposed to potassium aluminum tetrafluoride. I have observed several cases of bronchial hyperreactivity or asthma among workers exposed to this substance in their work (1). Potassium aluminum tetrafluoride is used as a flux powder in a process of joining aluminum sheets. There is a risk of inhalation of flux particles, most of them being respirable in size. Several exposed workers developed a persistent and worsening cough and wheezing during flux exposure, after a latency time of some months or more, and eventually bronchial hyperreactivity or asthma appeared. This lung affection seems primarily to affect workers with an atopic predisposition. Among workers who developed bronchial hyperreactivity or asthma, I failed to find specific immunoglobulin (Ig) E antibodies against the conjugates of potassium aluminum tetrafluoride with human serum albumin. Fluoride may be only irritating to the airways, but the exposure levels of potassium aluminum tetrafluoride that causes bronchial hyperactivity or asthma is lower than that causing airway irritation by fluoride exposure. Although no specific antibodies have been found, there seems to be an allergy-like reaction involved, indicated by the way the patients develop their illness and the selective way by which the bronchial hyperactivity or asthma of some workers worsens. Aluminum compounds are known to be strong allergy adjuvants and act as nonspecific enhancers of allergic reactions. G-proteins act as a signal carrier from the cell surface receptors to the interior of the cells and affect the histamine release response in the mast cells of an IgE-mediated allergy. In animal experiments, the combination of alumina and ovalbumin, when alumina was given after ovalbumin injections, substantially increased the serum IgE and IgG2a levels and the antigen-induced histamine release from mast cells (2). Furthermore, aluminum fluoride is a potent activator of G-proteins. Members of the heterotrimeric G-proteins are strongly activated by aluminum tetrafluoride (3). G-proteins form stable complexes with guanosine triphosphate and aluminum in the presence of fluoride ion (4). Aluminum fluoride has also been found to stimulate arachidonic acid release and thus increase the production of prostaglandin E2, which has a key role in airway inflammation (5). The cells in the bronchial lining, when exposed to potassium aluminum tetrafluoride, may also be stimulated to increasing the production of interleukins. This occurrence could primarily affect persons with a genetic phenotype that predisposes them for an enhanced ability to synthesize interleukin 4, 5, and 13 (6, 7). Potassium aluminum tetrafluoride may thus, through G-protein activation, have a nonspecific modulatory function in the IgE-mediated immune response. To my knowledge this model of an enhanced nonspecific allergy reaction has not been proposed in connection with occupational asthma due to exposure to potassium aluminum tetrafluoride.

Fur mites induce dermatitis associated with IgE hyperproduction in an inbred strain of mice, NC/Kuj

An inbred strain of mice, NC, has been introduced as an animal model for atopic dermatitis because the mice develop dermatitis associated with severe scratch preceded by elevated serum IgE level when kept in conventional conditions. Although hypersensitivity to some environmental factors is suggested to cause dermatitis, the precise factor remains unclear. As the mice maintained under conventional conditions were often infected with fur mites, we investigated whether an infection of fur mites induces skin lesions in NC. Infection with the fur mites induced NC to develop skin lesions associated with highly elevated serum IgE, whereas no obvious skin lesions were observed in BALB/c and C57BL/6, and the elevation of serum IgE level was minimal in these two strains of mice. The role of the fur mites in the manifestation of skin lesions and IgE hyperproduction was confirmed by eliminating the fur mites by treatment with ivermectin. In addition, the existence of specific IgE antibody to Myocoptes musculinus antigen in the sera of mite-infested NC was detected by the antigen-induced histamine release from bone marrow-derived cultured mast cells after sensitization with the serum. These results suggest that continuous exposure to fur mite antigen is a potential factor in the development of dermatitis in NC. We provide a new model system of antigen-induced dermatitis for investigating the role of IgE in eliciting dermatitis.

Effect of tetracosahexaenoic acid on the content and release of histamine, and eicosanoid production in MC/9 mouse mast cell.

6,9,12,15,18,21-Tetracosahexaenoic acid (24:6n-3) was isolated from a brittle star, Ophiura sarsi Lütken, at >95% purity to evaluate its physiological functions. The effects of 24:6n-3 on the production of leukotriene (LT)-related compounds such as LTB4, LTC4 and 5-hydroxyeicosatetraenoic acid, and the accumulation and release of histamine in an MC/9 mouse mast cell line were studied. We found that 24:6n-3 could inhibit the antigen-stimulated production of LT-related compounds as well as other n-3 polyunsaturated fatty acids (PUFA) such as eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3), which are major n-3 PUFA in fish oils; 24:6n-3 was also shown to reduce the histamine content in MC/9 cells at 25 microM (27% reduction from the control), and the effect was diminished with increase of the fatty acid concentration (up to 100 microM). These two n-3 PUFA, 20:5n-3 and 22:6n-3, also reduced the histamine content (16 and 20% reduction at 25 microM, respectively), whereas arachidonic acid (20:4n-6) increased it (18% increase at 25 microM). Spontaneous- and antigen-induced release of histamine was not influenced with these PUFA (at 25 microM). Ionophore-stimulated release of histamine was suppressed by the PUFA (13, 9, 15, and 11% reduction with 20:4n-6, 20:5n-3, 22:6n-3, and 24:6n-3, respectively). The patterns of the effects of 24:6n-3 on the synthesis of eicosanoids and histamine content were more similar to those of 22:6n-3 than 20:5n-3. From these results, 24:6n-3 can be expected to have anti-inflammatory activity and antiallergic activities similar to those of 22:6n-3.

Effect of TYB-2285 on Peritoneal Anaphylaxis in Passively Sensitized Rats

1. The effect of TYB-2285, a novel anti-inflammatory drug, was investigated on passive peritoneal anaphylaxis in rats, and compared with disodium cromoglycate (DSCG), amlexanox, ketotifen fumarate and tranilast. 2. As parameters of passive peritoneal anaphylaxis, histamine release into the peritoneal cavity and capillary permeability elicited by ascitis were measured. 3. TYB-2285 (10 mg/kg), when given intraperitoneally at 0.5, 1 and 2 min before antigen challenge, inhibited anaphylactic histamine release by 36.2%, 57.5% and 52.6%, respectively. TYB-2285 also inhibited capillary permeability by 20.9%, 57.6% and 49.0%, respectively. 4. DSCG (10 mg/kg), given intraperitoneally 0.5 min before challenge, inhibited histamine release and capillary permeability by 79.6% and 57.6%, respectively. 5. Amlexanox (10 mg/kg), given intraperitoneally 0.5 min before challenge, inhibited histamine release and capillary permeability by 85.6% and 74.8%, respectively. 6. A time-course study showed that TYB-2285 (30 mg/kg) was effective for 30 min after oral administration. A dose–response study suggested that the inhibitory effect of TYB-22585 (postoperatively) on histamine release during PPA reached a plateau at 10 mg/kg. 7. In passive peritoneal anaphylaxis in vitro, TC-1121 and TC-1122, metabolites of TYB-2285, inhibited antigen-induced histamine release at 10 −7 to 10 −5 M in a dose-dependent manner, whereas TYB-2285 itself and other major metabolites of TYB-2285, TC-286 and TC-326, did not inhibit histamine release, even at 10 −4 M.

Novel antiallergic agents. Part I: Synthesis and pharmacology of pyrimidine amide derivatives

We have synthesized many pyrimidine amide derivatives. Novel pyrimidine bis-glycolic amide derivatives showed moderate inhibition in the rat passive cutaneous anaphylaxis (PCA) assay by oral administration. Among these compounds, 2,4-bis(methoxyacetylamino)-6-piperidinopyrirnidine (2i) exhibited significant inhibition. However the compound (2i) did not inhibit antigen-induced histamine or SRS-A release from lung fragments of the guinea-pig at less than 10−4 M. Derivatives of 2i have also notable or moderate activity in the rat PCA assay. Compound 2h which has no oxygen atom at the α-position of the amide carbonyl group and, compound 17 which has no amide carbonyl group, showed no inhibition in the rat PCA assay. We supposed that both the amide carbonyl group and the oxygen atom at α-position of the amide carbonyl group play an important role in inhibiting the rat PCA reaction. These pyrimidine bis-glycolic amide derivatives have a novel structure and unique activity which suggests they may be potentially useful in the treatment of allergic diseases.

Inhibitory effects of rupatadine on mast cell histamine release and skin wheal development induced byAscaris suum in hypersensitive dogs

The present studies were performed to compare the cutaneous antiallergic effects of rupatadine, a new potent dual antagonist of histamine and platelet-activating factor (PAF), with those of loratadine (an H1-antihistamine) and SR-27417A (a PAF antagonist). Two experimental models were used: an in vivo skin challenge by Ascaris suum extract administered intradermically in conscious hypersensitive dogs and an in vitro assay of Asc S 1 antigen-induced histamine release from isolated canine skin mast cells. In antigen-induced skin inflammation, both rupatadine and loratadine administered orally inhibited wheal formation in a dose-dependent manner at the studied doses. At the 0.1 mg/kg dose, maximum inhibition values for rupatadine and loratadine were similar, but the effect of rupatadine lasted 24 h, whereas loratadine's effect disappeared after 8 h. At the 1 mg/kg dose, the two compounds behaved similarly, with maximum effects of about 65% (4 h after treatment) and activity lasting more than 24 h in both cases. At the 10 mg/kg dose, rupatadine and loratadine exhibited maximum effects of 84 and 64% in wheal inhibition 2 and 4 h after drug administration, respectively. SR-27417A did not inhibit ascaris-induced wheal at the doses studied (1 and 10 mg/kg p.o.). In isolated canine skin mast cells, rupatadine and loratadine inhibited antigen-induced histamine release in a concentration-dependent manner. Rupatadine was more potent than loratadine at each concentration studied (100 nM–30 μM). Maximum inhibitory effects were 83 and 67% for rupatadine and loratadine, respectively, after a 30 μM concentration. Rupatadine, with an IC50 value of 5.3 μM, was about fourfold more potent than loratadine, with an IC50 value of 19 μM. SR-27417A exhibited no effect in our experimental model. Moreover, neither loratadine or rupatadine showed cytotoxic or prodegranulating effects at any concentration, whereas SR-27417A was cytotoxic at the highest concentration (30 μM). Thus, rupatadine is effective in controlling inflammatory reactions in dog skin and the effect may be partly due to its modulation of mast cell degranulation, but not to its PAF-antagonist properties. Drug Dev. Res. 44:49–55, 1998. © 1998 Wiley-Liss, Inc.

Peripheral changes and neuropathic pain after chronic trigeminal nerve injuries

The involvement of C-fiber afferent pathways in urinary frequency and pain associated with painful bladder syndrome raises the possibility of multiple targets for the treatment of this disease. Using an in vivo measurement of bladder activity as well as whole-cell patch clamp recording techniques to examine the properties of bladder afferent neurons in animal models of chronic cystitis, we have documented that tetrodotoxin-resistant sodium channels encoded by the Nav 1.8 (PN3/SNS) gene and nitric oxide acting via a cyclic guanosine monophosphate (cGMP)-dependent mechanism are important in modulating bladder pain responses. Thus, suppression of C-fiber afferent nerve activity by blocking specific sodium channels, elevating nitric oxide levels, or activating cGMP-dependent pathways might represent novel strategies for the treatment of symptoms in patients with painful bladder syndrome. Another treatment strategy is suppression of release or activity of proinflammatory agents that can cause normally unexcitable C-fiber afferents to become hyperactive or hyperexcitable. This approach to management of bladder pain was tested in patients with painful bladder syndrome by examining the effectiveness of the antiallergic agent suplatast tosilate (IPD-1151T), which suppresses urinary frequency in a rat model of cystitis. IPD-1151T is an immunoregulator that suppresses cytokine production in T-helper 2 cells and inhibits immunoglobulin E antibody formation and antigen-induced histamine release from mast cells. Preliminary data from an open-label clinical trial showed that 16 of 23 (70%) patients responded to treatment with IPD-1151T (300 mg/day orally for 12 months). The finding that expression of platelet-derived endothelial cell growth factor, which can activate mast cells, was lower in the bladder of responders than nonresponders indicates that bladder levels of platelet-derived endothelial cell growth factor may be a useful marker for this disease.

Inhibition of antigen-induced airway hyperresponsiveness by ultralow molecular-weight heparin.

Unfractionated heparin (UF-heparin) has been shown to prevent antigen-induced airway hyperresponsiveness (AHR), but it is ineffective when administered after the antigen challenge. We hypothesized that the failure of UF-heparin to modify postantigen AHR might depend on molecular weight. We therefore studied the effects of UF-heparin and three low-molecular-weight heparin fractions (medium-molecular-weight heparin [MMWH]; low-molecular-weight heparin [LMWH]; and ultralow-molecular-weight heparin [ULMWH]) on antigen-induced AHR and histamine release in bronchoalveolar lavage fluid (BALF). Specific lung resistance (SRL) was measured in 20 allergic sheep before, immediately after, and up to 2 h after challenge with Ascaris suum antigen. Airway responsiveness was expressed as the cumulative provocative dose of carbachol, in breath units, that increased SRL by 400% (PD400). PD400 was determined before and 2 h after antigen, both without and after treatment with aerosolized UF-heparin (1,000 U/kg) and various heparin fractions (0.04 mg/kg to 5 mg/kg) administered after the antigen challenge. Inhaled UF-heparin (n = 4), MMWH (n = 4), and LMWH (n = 6) failed to modify postantigen AHR when administered after the challenge. Only ULMWH (n = 6) inhibited postantigen AHR in a dose-dependent manner (percent protection ranged from 31% to 139%). In eight additional sheep, histamine in BALF was measured with a radioimmunoassay (RIA) before and after the segmental antigen challenge, without and after pretreatment with inhaled UF-heparin, LMWH, or ULMWH. Inhaled UF-heparin and LMWH inhibited antigen-induced histamine release as measured in BALF by 81% and 75%, respectively; whereas ULMWH was ineffective in this respect. We conclude that: (1) modification of antigen-induced AHR by fractionated heparins is molecular-weight dependent; and (2) only ULMWH attenuates AHR when administered after antigen challenge, via an unknown mast-cell-independent action.

Pharmacological Studies on the Novel Antiallergic Drug HQL-79: II. Elucidation of Mechanisms for Antiallergic and Antiasthmatic Effects

The effects of 4-benzhydryloxy-1-{3-(1H-tetrazol-5-yl)-propyl}piperidine (HQL-79), a newly developed antiallergic drug, on various chemical mediators and on chemical mediator release were investigated. Orally administered HQL-79 strongly inhibited the histamine-induced skin reaction in rats, and histamine- and 5-hydroxytryptamine (5-HT)-induced bronchoconstriction in guinea pigs. HQL-79 inhibited antigen-induced release of leukotriene (LT) B4, LTC4, histamine and prostaglandin (PG) D2 from the chopped lung tissues of actively sensitized guinea pigs. On the other hand, release of PGE2, one of the bronchoprotective prostanoids, was significantly enhanced by HQL-79. In an in vivo experiment, chronic administration of HQL-79 clearly reduced PGD2 contents and enhanced PGE2 contents in the lungs of repeatedly antigen-exposed guinea pigs. In biochemical studies, HQL-79 inhibited mouse spleen PGD synthase in a concentration-dependent manner. None of the antiallergics such as epinastine, terfenadine, oxatomide and cetirizine inhibited the PGD synthase. HQL-79 did not affect PGE synthase in sheep vesicular gland microsomes. These results suggest that antiallergic and antiasthmatic effects of HQL-79 could be ascribed to antihistaminic- and anti-5-HT effects, chemical mediator release inhibition, PGE2-release enhancement and PGD synthase inhibition. It is considered, in particular, that the differential modulation of PGD2 and PGE2 production is a conspicuous pharmacological feature of HQL-79.

Effect of cetirizine on antigen-induced tracheal contraction of passively sensitized guinea pigs.

Cetirizine dihydrochloride (cetirizine), a potent histamine H1-receptor antagonist, has been developed as an anti-allergy drug. The anti-allergic effects and mechanism of cetirizine were studied using in vitro assay systems. We investigated the effect of cetirizine on antigen-induced contractions of isolated tracheal strips and on chemical mediator release from antigen-stimulated lung chips taken from passively sensitized guinea pigs. We examined the antigen-induced mobilization of Ca2+ in MC/9 mast cells sensitized with IgE. Cetirizine inhibited the antigen-induced contraction of isolated guinea-pig trachea concentration dependently. Pyrilamine, another histamine H1-receptor antagonist, delayed the response but did not change the maximum amplitude. Cetirizine at the concentration of 3 microM also inhibited the antigen-induced release of histamine, leukotriene D4, and leukotriene E4 from guinea pig lung chips. Furthermore, it inhibited the antigen-induced Ca2+ increase in MC/9 mast cells, whereas pyrilamine did not. These findings suggest that one anti-allergic mechanism of cetirizine may inhibit mediator release which is, at least partially, mediated by a decrease in the transient Ca2+ influx in mast cells.

Inhibitory effect of tyrosine kinase inhibitors on antigen-induced tracheal contraction and histamine release in guinea pigs.

We examined the effect of two different types of tyrosine kinase inhibitor, herbimycin A and genistein, on antigen-induced tracheal contraction and antigen-induced histamine release from the trachea in sensitized guinea pigs in vitro. Herbimycin A (1-10 microM) and genistein (1-10 microM) significantly inhibited antigen-induced tracheal contraction, compared with control. Additionally, herbimycin A (1-10 microM) and genistein (3-10 microM) significantly inhibited antigen-induced histamine release from the trachea in a concentration-dependent manner, compared with control. On the contrary, herbimycin A and genistein did not suppress acetylcholine- and histamine-induced tracheal contraction. We concluded that herbimycin A and genistein inhibit antigen-induced tracheal contraction without inhibiting smooth muscle contractility, and these inhibitory effects are due to, at least partially, inhibiting histamine release from tracheal mast cells.

Selective potentiation of IgE-dependent histamine release from rat peritoneal mast cells by stem cell factor

Effect of stem cell factor on histamine release from rat peritoneal mast cells was studied. Although stem cell factor did not evoke histamine release by itself, it clearly potentiated histamine release from sensitized mast cells caused by antigen, anti-IgE and concanavalin A. However, stem cell factor did not affect histamine release caused by compound 48/80, calcium ionophore A23187 and substance P. Although maximum potentiation of antigen-induced histamine release by stem cell factor was accomplished after 1–10 minute-preincubation, potentiation was declined after a longer incubation period. Potentiation of histamine release by phosphatidylserine and non-mast cells in the rat peritoneal cavity was incubation time-dependent. Potentiation by stem cell factor was additive to that by phosphatidylserine or non-mast cells. These results indicate that stem cell factor selectively potentiates IgE-dependent histamine release from rat peritoneal mast cells, and suggest that the mechanism involved is distinct from that of phosphatidylserine or non-mast cells in the rat peritoneal cavity.

ANTIGEN AVOIDANCE IN A MOUNTAIN ENVIRONMENT: INFLUENCE ON BASOPHIL RELEASABILITY IN CHILDREN WITH ALLERGIC ASTHMA

Prolonged stays in a mite-free environment by mite-sensitive children with asthma produce a significant improvement in bronchial hyperreactivity and in antigen-induced histamine release from basophils.

Some anti-allergic and anti-inflammatory actions of 2-N-carboxamidinonormianserin (FCC5).

The aims of these studies were to examine the effects of FCC5 (2-carboxamidino-1,2,3,4,10,14b-hexahydrodibenzo (c,f) pyrazino (1,2,-a) azepine HCl), an analogue of mianserin, on immediate type hypersensitivity reactions in-vitro. The actions of FCC5 were examined on the Schultz-Dale reaction of guinea-pig ileum and on histamine and leukotriene release from human- and guinea-pig-sensitized lung fragments. FCC5 (applied topically) was assessed for anti-inflammatory activity in-vivo against phorbol-12-myristate-13-acetate (PMA)-induced oedema in the mouse ear. FCC5 (IC50 = 0.17 microM) was a potent inhibitor of the Schultz-Dale reaction in-vitro, as assessed by a concentration-dependent attenuation of egg albumin-induced contractions of sensitized guinea-pig isolated ileum. Using human and guinea-pig isolated sensitized lung fragments, FCC5 (1-100 microM) attenuated antigen-induced release of sulphidopeptidoleukotrienes and histamine. FCC5 (50 micrograms topically) resembled mianserin and indomethacin in attenuating PMA-induced mouse ear inflammation. These properties together with previously published evidence of long lasting antihistamine properties in-vivo, suggest that FCC5 has therapeutic potential as an anti-allergic agent, especially in pathological conditions where an inflammatory component is present.

The Effects of Tumour Necrosis Factor α on Mediator Release from Human Lung

Summary: Although tamour necrosis factor α (TNFα) may be involved in the pathology of asthma, little is known about its role in mediator release from inflammatory cells in human lung. We investigated whether TNFα induced histamine release from mast cells in human chopped lung tissue and whether it modulated antigen-induced release of histamine and leukotrienes C 4/D 4/E 4 from passively sensitized lung tissue. Spontaneous histamine release in the presence of 1 nM TNFα for up to 4 h at 37°C was not significantly different from spontaneous histamine release alone (6.1±1.3% and 6.1±1.5% of total tissue histamine at 4 h respectively; n=3). Lung tissue was passively sensitized to the house dust mite Dermatophagoides pteronyssinus by incubating it in serum from an atopic volunteer donor for 3 h at 37°C. Treatment of the sensitized lung tissue with 1 nM TNFα for 60 min prior to challenge with a low concentration (1.8 AU) of D. pteronyssinus caused a significant increase in the amount of histamine release induced by the antigen from 0.2±0.6% to 1.9±1.0% of total tissue histamine ( P=0.045, n=6). The release of leukotriene C 4/D 4/E 4 induced by the same concentration of antigen was not significantly changed by the TNFα treatment (39.5±9.1 and 55.6±17.7 pg/100 μl supernatant sample respectively; n=6). These results suggest that TNFα may be involved in potentiation of histamine release in allergic asthma, particularly in the presence of low antigen concentrations.

Mechanism of histamine release by endothelin-1 distinct from that by antigen in mouse bone marrow-derived mast cells

The mechanisms of endothelin-1-induced histamine release were examined and compared with those responsible for antigen-induced release by using passively sensitized mouse bone marrow-derived mast cells and various drugs that may influence histamine release. The following results were obtained: (1) Although islet-activating protein potently inhibited endothelin-1-induced histamine release, it did not affect the antigen-induced release. (2) Histamine release induced by endothelin-1 was relatively more sensitive to ethylenediaminetetraacetic acid than that induced by antigen, although, extracellular Ca 2+ is a requisite for both types of the release. (3) ( 8R ∗, 9S ∗, 11S ∗ )-(−)-9-hydroxy-9-methoxycarbonyl-8-methyl- 2,3,9,10-tetrahydro-8, 11-epoxy-1 H,8 H,11 H-2,7b,11a-triazadibenzo[ a,g]cycloocta[ c,d,e]trinden-1-one and ( 8R ∗, 9S ∗, 11S ∗ )-(−)-9-hydroxy-9-methoxycarbonyl-8-methyl-14- n-propoxy- 2,3,9,10-tetrahydro-8,11-epoxy-1 H,8 H,11 H-2,7b,11a-triazadibenzol[ a,g]cycloota-[ c,d,e]trinden-1-one, which possibly inhibit protein kinases, strongly inhibited antigen-induced histamine release, while these drugs alone did not inhibit endothelin-1-induced release. (4) Staurosporine, a non-selective protein kinase inhibitor, prevented the elevation of cytosolic Ca 2+ concentrations induced by antigen, whereas that induced by endothelin-1 was not influenced; histamine release induced by either stimulus was greatly inhibited by the drug. These results indicate and/or suggest that some biological events induced by endothelin-1 leading to histamine release are different from those involved in the histamine release induced by antigen.

Studies on anti-allergic action of AH 21-132, a novel isozyme-selective phosphodiesterase inhibitor in airways.

The effects of AH 21-132, a type III and IV phosphodiesterase (PDE) inhibitor, on allergic reactions in the airway were studied by comparing them with the effects of rolipram, a type IV PDE inhibitor, and aminophylline, a non-selective PDE inhibitor. The following results were obtained: 1) AH 21-132, rolipram and aminophylline inhibited the antigen-induced contraction of isolated guinea pig tracheal muscle in vitro. 2) AH 21-132 and aminophylline inhibited antigen-induced histamine release from human lung tissue fragments. 3) Antigen-induced accumulation of inflammatory cells including eosinophils and macrophages in mice bronchoalveolar lavage fluid was clearly inhibited by AH 21-132 and rolipram, but not by aminophylline. 4) AH 21-132, rolipram and aminophylline inhibited immediate phase bronchocostriction induced by either an intravenous or an aerosol challenge of antigen in guinea pigs. 5) AH 21-132 and rolipram inhibited the aeroantigen challenge-induced late phase increase in the airway resistance in guinea pigs, but aminophylline did not. These results suggest that AH 21-132 has an anti-allergic effect in the airway and that these actions may be beneficial for the treatment of allergic bronchial asthma.

Classification and biological distribution of histamine receptor sub-types

The distribution and classification of histamine receptors in mammalian and avian tissues have been summarized in Tables 1-4. It is evident that histamine receptors are present on a number of morphologically distinct cell types and the proportion of cells bearing H1- and H2-receptors varies not only with the species but also with the cell source. The pharmacological receptors mediating mepyramine-sensitive histamine responses have been defined as H1-receptors. Receptors mediating mepyramine-resistant, but burimamide or metiamide-sensitive histamine responses have been classified as H2-receptors. Histamine responses mediated via H2-receptors seem to involve the adenylcyclase system resulting in elevation of intracellular cyclic-AMP level, which is susceptible to burimamide blockade but insensitive to beta-adrenergic blocking agents. This mode of action of histamine involving H2-receptors and the adenyl cyclase system has been shown to stimulate the mammalian heart; promote gastric acid secretion; inhibit antigen-induced histamine release from leucocytes and inhibit lymphocyte-mediated cytotoxicity. It can further be concluded that both H1- and H2-receptors are widely distributed throughout the animal body in the gastro-intestinal, reproductive, respiratory and cardiovascular systems, nervous system and on mast cells and blood leucocytes. In these tissues, histamine receptors play an important role in physiological, immunological and immunopathological processes. Interaction of histamine with both H1- and H2-receptors in varying proportions modulates the overall manifestation of cardiovascular and respiratory syndromes during certain immunopathological conditions (e.g. inflammation, allergy and anaphylaxis). Histamine receptors also appear to play and important role in the development of immuno-competence and immunity.

Involvement of apamin-sensitive K+ channels in antigen-induced spasm of guinea-pig isolated trachea.

1. In order to examine whether K+ channels play a role in antigen-induced airway responses, the effect of K+ channel blockers on antigen-induced airway smooth muscle contraction and mediator release was examined in vitro in guinea-pigs actively sensitized with ovalbumin (OA). 2. Tracheal strips from sensitized animals were suspended in organ baths under a resting tension of 1 g and isometric tension was continuously measured. Cumulative concentration-response curves to OA (0.1-1000 ng ml-1) or histamine (10 nM-1 mM) were obtained in the presence and absence of K+ channel blockers. 3. OA (10, 100 or 1000 ng ml-1) was incubated with minced lung tissues from the same animals for 15 min in the presence and absence of K+ channel blockers, and released histamine and leukotriene C4 (LTC4) in the incubating medium were measured. 4. Apamin, a small conductance Ca(2+)-activated K+ channel (PK,Ca) blocker, (0.1, 0.3 and 1 microM) significantly inhibited OA-induced smooth muscle contraction, while charybdotoxin (ChTX, 10 nM), an intermediate and large conductance PK,Ca blocker, and iberiotoxin (IbTX, 3 nM), a large conductance PK,Ca blocker, were without effect. Apamin (0.3 microM) had no effect on exogenously administered histamine-induced airway smooth muscle contraction, suggesting that the inhibition of OA-induced contraction by apamin did not occur at the smooth muscle level. 5. The inhibition of OA-induced contraction by apamin (0.3 microM) was not significantly affected by pretreatment with a leukotriene antagonist, ONO-1078 (10 microM), but was abolished by pretreatment with a histamine H1-receptor blocker, pyrilamine (1 microM). 6. Apamin by itself (up to 0.1 MicroM) had no effect on spontaneous histamine release from minced lung tissues. Histamine release induced by low and intermediate concentrations of OA (10 and 100 ng ml-1)was significantly suppressed by apamin pretreatment (P<0.05 and P<0.001), whereas LTC4 release was not affected. ChTX (0.1 MicroM) and IbTX (10 nM) had no significant effect on either spontaneous or OA (100 ng ml-1)-induced histamine release.7. These results suggest that apamin partially but substantially inhibits antigen-induced smooth muscle contraction, presumably by inhibiting antigen-induced histamine release from airway mast cells through small conductance PKca closure.

IgE-receptor activated chloride uptake in relation to histamine secretion from rat mast cells.

1. Antigen-stimulated histamine secretion from rat peritoneal mast cells was inhibited when extracellular chloride was replaced by either isethionate or gluconate anions, but the histamine release still remained quite substantial. 2. Rat peritoneal mast cells take up 36Cl and the uptake reaches a steady state after 60 min incubation with the isotope. At steady state, the intracellular chloride level in the cells was calculated to be 29 +/- 11.5 mM. 3. The chloride uptake in mast cells was exponential with a rate constant of 0.036 min-1 in resting cells. When the cells were stimulated with antigen, and rate constant for chloride uptake increased to 0.90 min-1: an increase of 25 fold. Under identical experimental conditions histamine release increased 3 fold. 4. The rate of chloride uptake in either resting cells or in antigen-stimulated cells was not changed when the extracellular medium was nominally calcium-free but histamine release was almost completely inhibited in the absence of extracellular calcium. 5. The putative chloride channel blocker DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid) 0.3 to 30 microM, produced a concentration-related inhibition of antigen-stimulated histamine secretion but DIDS (30 microM) did not inhibit the antigen-stimulated increase of chloride uptake. 6. The cyclic AMP analogue, dibutyryl cyclic AMP (1 mM) produced a delayed increase in chloride uptake in resting mast cells but neither dibutyryl cyclic AMP nor 8-bromo cyclic AMP per se induced any histamine secretion. 7. Ouabain (1 mM) which inhibits the Na+/K+ ATPase in rat peritoneal mast cells, failed to affect the uptake of chloride in resting mast cells. 8. The Na/K/2C1-cotransport inhibitor, furosemide (0.7 mM), slowed the unstimulated chloride uptake in resting mast cells and abolished the increased antigen-induced chloride uptake when added together with antigen. In contrast, spontaneous and antigen-induced histamine release were unaffected by the presence of furosemide. However, when furosemide was added to the cell suspension 5 min before stimulation, furosemide was without effect on the antigen-induced chloride uptake.9. In addition to the chloride uptake mediated by chloride channels which may be related to the mechanism of histamine secretion, crosslinking of the high affinity membrane receptors for IgE is followed by a fast chloride uptake that is likely to occur through a furosemide-sensitive Na/K/2C1-cotransporter.