The effect of nedocromil on weal reactions in human skin.

1. Nedocromil 2% iontophoresed into human skin had no effect on wealing produced by intradermal histamine, 48/80 or house dust mite antigen. 2. Iontophoresis of 0.002-2% nedocromil itself resulted in dose-related wealing. 3. This wealing was reduced by 62 +/- 8% s.e. mean by the H1-receptor antagonist terfenadine which decreased histamine wealing by 68 +/- 2% s.e. mean. 4. Nedocromil may therefore act as a weak agonist on a skin mast cell receptor concerned with histamine release.     

Nedocromil sodium inhibits antigen-induced contraction of human lung parenchymal and bronchial strips, and the release of sulphidopeptide-leukotriene and histamine from human lung fragments.

1. The effects of nedocromil sodium on antigen-induced release of sulphidopeptide-leukotrienes and histamine from passively sensitized fragments of human lung, and on antigen-induced contraction of sensitized strips of human lung parenchyma and bronchus, have been studied. 2. Nedocromil sodium 0.1 and 1 microM inhibited leukotriene release from fragments of human lung by 30% and 38% respectively, and histamine release by 43% for both concentrations, but 10 microM was ineffective. The lung fragments, which were passively sensitized to house dust mite, Dermataphagoides pteronyssinus, in control experiments released leukotrienes (6.58 +/- 0.12 nmol equiv. leukotriene C4 per g, n = 6) and histamine (10.3 +/- 1.8 of total tissue histamine, n = 5) when challenged with house dust mite extract. 3. Isolated strips of human lung parenchyma, passively sensitized to D. pteronyssinus, contracted when treated with house dust mite extract to a mean value of 40% of the maximal histamine response for each strip. Nedocromil sodium 0.1 and 1 microM inhibited these contractions by 50% and 70% of the control response, but 10 microM had no inhibitory effect. 4. Isolated rings from human bronchus, also passively sensitized to D. pteronyssinus, contracted when treated with house dust mite extract to a mean value of 86% of the maximal histamine response. Nedocromil sodium 1 microM, but not 0.1 or 10 microM, inhibited contractions by 48% of the control response. 5. The therapeutic effects of nedocromil sodium in allergic asthma may depend, partly, on its inhibition of antigen-induced release of leukotrienes and histamine in human lung and its consequent inhibition of antigen-induced contractions of parenchymal and bronchial tissue.     

Role of endogenous serotonin and histamine in the pathogenesis of gastric mucosal lesions in unanaesthetised rats with a single treatment of compound 48/80, a mast cell degranulator.

In unanaethetised rats with a single injection of compound 48/80, a mast cell degranulator (0.75 mg kg-1, i.p.), gastric lesions occurred with increased serum serotonin and histamine levels and reduced gastric mucosal blood flow at 0.5 h after the injection and developed at 3 h. Pretreatment with either cyproheptadine (a serotonin and histamine antagonist) or methysergide (a serotonin antagonist) prevented the formation of gastric mucosal lesions with attenuation of reduced gastric mucosal blood flow at 0.5 h after compound 48/80 injection, while pretreatment with either amitriptyline (a selective inhibitor of histamine release from mast cells), tripelennamine (a histamine H1-receptor antagonist), famotidine (a histamine H2-receptor antagonist) or cimetidine (a histamine H2-receptor antagonist) had no effect. Pretreatment with either cyproheptadine, methysergide, amitriptyline or tripelennamine prevented the development of gastric mucosal lesions at 3 h after compound 48/80 injection, while pretreatment with either famotidine or cimetidine had no effect. These results indicate that in unanaesthetised rats with a single compound 48/80 treatment, acutely released endogenous serotonin causes gastric mucosal lesions, while released endogenous histamine mainly contributes to the lesion development and that gastric acid plays little role in the pathogenesis of the compound 48/80-induced acute gastric lesions.     

Evidence of mast-cell histamine being mitogenic in intact tissue

We have reported previously that secretion by connective tissue mast cells (MCs) causes mitogenesis in adjacent cells in diverse rat tissues. In cultured rat mesentery there was a spontaneous release of about 45% of the histamine in 2 days, and a spontaneous marked increase in basal proliferation of the mesentery. The MC secretagogues, compound 48/80 and polymyxin B, released additional histamine and stimulated mitogenesis further. In contrast, 48/80 added to cultures of guinea-pig mesentery, the MC of which are unresponsive to the drug, did not affect the basal proliferation. However, exogenous histamine at 10(-10) M mitogenically stimulated the cultured guinea-pig mesentery. A histamine H2-receptor antagonist, which itself was mitogenically inert, significantly suppressed the 48/80-induced MC-mediated mitogenesis in rat mesentery in vivo and in vitro. On the other hand, a histamine H1-receptor antagonist did not affect this MC-mediated mitogenesis in rat. Our findings indicate that histamine is one of possibly several mitogens which are released or activated by the secreting MC.     

Vascular reactions to histamine and compound 48/80 in human skin: suppression by a histamine H2-receptor blocking agent.

1 The ability of a specific competitive histamine H2-receptor antagonist, cimetidine, to inhibit vascular responses to histamine in human skin provides new evidence that skin blood vessels possess histamine H2 receptors. 2 Simultaneous systemic administration of cimetidine and chlorpheniramine (an H1-receptor antagonist) was more effective than either drug alone in inhibition of the erythematous reaction both to exogenous histamine, and endogenous histamine secreted by skin mast cells in response to compound 48/80. 3 These results suggest that combined therapy of histamine-mediated skin diseases included urticaria and dermatitis using a combination of H1- and H2-histamine receptor antagonists may be more effective than either class of drug alone.     

Histamine is released from skin by substance P but does not act as the final vasodilator in the axon reflex.

We have explored in man the hypothesis that histamine released from dermal mast cells by neurotransmitters from afferent nerves contributes to vasodilatation of the axon reflex. The ability of substance P to release histamine from human skin in vivo, and the effects of a histamine H1-receptor antagonist on capsaicin-induced axon reflex flares were studied. Intradermal injections of substance P (50 pmol) produced a weal and flare response which was associated with increased histamine concentration in blood draining the site (mean plasma histamine concentration before injection 0.17 +/- 0.02 ng ml-1 (+/- s.e.mean), concentration one minute after injection 1.26 +/- 0.28 ng ml-1, n = 6). Terfenadine, an H1-receptor antagonist, had no effect on the flare response to intradermal injection of capsaicin at a dose which inhibited by more than 60% the flare response to exogenous histamine and to histamine released from dermal mast cells by substance P. Substance P releases histamine from human skin in vivo. However, whatever the nature of the neurotransmitter released from afferent nerves during the axon reflex, it does not produce vasodilatation through release of histamine from dermal mast cells. Histamine may still contribute to the flare by initiation of the reflex.     

The effect of indomethacin on the kinetics of histamine, 48/80 and antigen wealing.

1. The kinetics of weal formation and disappearance following intradermal injection of histamine, compound 48/80 and antigen were measured in indomethacin and inert geltreated human forearm skin. 2. Rates of formation went in descending order for histamine, 48/80 and antigen; rate constants of disappearance for equal sized weals were the same for histamine and 48/80 but were much less for antigen. The corresponding half-lives were 77, 73 and 160 min for histamine, 48/80 and antigen weal disappearance respectively. 3. Cyclo-oxygenase inhibition by topical indomethacin had no effect either on the immediate weal and flare responses or on the rates of formation and disappearance of the weals. 4. These findings together with previous studies using H1-receptor antagonists indicate that 48/80 acts by histamine release but that antigen releases both histamine and an additional material or materials which are not related to cyclo-oxygenase activity. 5. Exacerbation of chronic idiopathic urticaria by cyclo-oxygenase inhibitors is therefore likely to be part of the urticarial disease process.     

Histamine decreases myogenic tone in rat cerebral arteries by H2-receptor-mediated KV channel activation, independent of endothelium and cyclic AMP

Adenosine produces bronchoconstriction in allergic rabbits, primates, and humans by activating adenosine A(1) receptors. Previously, it is reported that a high dose of L-97-1, a water-soluble, small molecule adenosine A(1) receptor antagonist, blocks early and late allergic responses, and bronchial hyper-responsiveness to histamine in a hyper-responsive rabbit model of allergic asthma. Effects of a lower dose of L-97-1 are compared to montelukast, a cysteinyl leukotriene-1 receptor antagonist on early allergic response, late allergic response, bronchial hyper-responsiveness, and inflammatory cells in bronchoalveolar lavage (BAL) fluid following house dust mite administration. Rabbits received intraperitoneal injections of house dust mite extract within 24 h of birth followed by booster house dust mite injections. Hyper-responsive rabbits received aerosolized house dust mite (2500 allergen units), 1 h after intragastric administration of L-97-1 (1 mg/kg) or montelukast (0.15 mg/kg) and lung dynamic compliance was measured for 6 h. Lung dynamic compliance was significantly higher following L-97-1 at all time points and with montelukast at 60-300 min following house dust mite (P<0.05). L-97-1 blocks both early and late allergic responses. Montelukast blocks only the late allergic response. Both L-97-1 and montelukast significantly blocked bronchial hyper-responsiveness at 24 h (P<0.05). Both L-97-1 and montelukast significantly reduced BAL eosinophils at 6 h and neutrophils at 6 and 24 h (P<0.05). L-97-1 significantly reduced BAL lymphocytes at 6 and 24 h (P<0.05). Montelukast significantly reduced BAL macrophages at 6 and 24 h (P<0.05). By blocking both bronchoconstriction and airway inflammation, L-97-1 may be an effective oral anti-asthma treatment.     

Effects of SK&F 93944 (Temelastine), a potent histamine H1-receptor antagonist in pharmacologic and antigen-induced bronchoconstriction

SK&F 93944, a previously reported non-sedating histamine H1-receptor antagonist, was evaluated for its ability to block pharmacologic-and antigen-induced bronchoconstriction. In the isolated guinea pig trachea, SK&F 93944 (10(-9)-10(-7) M) produced a concentration-dependent inhibition of contractions produced by histamine (pKB = 9.5). Another histamine antagonist, mepyramine (10(-8)-10(-6) M), was less potent (pKB = 8.5). SK&F 93944 (10(-8), 10(-7) M) also significantly depressed the rapid initial phase of antigen-induced contraction of the guinea pig trachea from animals actively sensitized to ovalbumin, while having no effect on the later, more protracted phase of the contractile response. In anesthetized mongrel dogs, selective inhibition of histamine (20 micrograms/kg, i.v.)-induced bronchoconstriction was achieved by SK&F 93944 in doses as low as 30 micrograms/kg, i.v. Terfenadine, a purportedly selective histamine H1-receptor antagonist, blocked both histamine and acetylcholine-induced bronchoconstriction at doses similar to SK&F 93944. In mongrel dogs natively allergic to Ascaris suum antigen, pretreatment with aerosols of either SK&F 93944 or mepyramine (1%; 50 tidal breaths) significantly inhibited bronchospasm elicited by increasing aerosol concentrations of antigen. Thus, SK&F 93944 is a highly potent, selective histamine H1-receptor antagonist which is efficacious vs. pharmacologic and antigen-induced bronchoconstriction.     

Possible role of mast cells in cineole-induced scratching behavior in mice.

We examined the scratch (itch) inducing effect of 1,8-cineole (cineole), a monoterpene oxide present in many plant essential oils and the possible role of mast cells in the response. Subcutaneous injection of cineole (10, 20 and 40 microl/site) or the mast cell degranulating agent, compound 48/80 (25, 50 and 100 microg/site) into the rostral back of mice induced a scratching behavior. This response of cineole as well as that of 48/80 was markedly suppressed in mice subjected to mast cell desensitization by repeated injections of 48/80. The cineole-induced scratching was also significantly diminished in animals pretreated with diphenhydramine, the histamine H1-receptor antagonist or cyproheptadine, the dual histamine/serotonin-receptor antagonist. Furthermore, the scratch-inducing effect of cineole was greatly reduced in mice that received the opioid antagonist naloxone or the selective adenosine A1-receptor agonist, N6-cyclopentyladenosine (CPA), but not the more selective adenosine A2-receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA). The data suggest a likely role for mast cells in cineole-induced scratching behavior of mice, possibly involving adenosinergic and opioidergic mechanisms.     

Evaluation of the role of Histamine H1- and H2-receptors in cutaneous inflammation in the guinea-pig produced by histamine and mast cell degranulation.

1 The role of histamine H1- and H2-receptors in mediating the cutaneous inflammatory response produced by exogenous histamine and the release of endogenous histamine from mast cells has been investigated by a method which permits simultaneous, quantitative measurement of vasodilatation, vascular permeability and oedema formation. 2 Histamine and the selective H1-receptor agonist, 2-(2-aminoethyl) pyridine, both produced vasodilatation, increased vascular permeability and oedema formation whereas the selective H2-receptor agonist, dimaprit, produced only vasodilatation. 3 Mepyramine and cimetidine both reduced the vasodilatation response to histamine, the combination of antagonists being superior to either antagonist alone. Mepyramine (but not cimetidine) virtually abolished extravascular albumin accumulation and oedema formation. 4 Mepyramine and cimetidine both reduced the vasodilatation response produced by active cutaneous anaphylaxis and compound 48/80. However, mepyramine was less effective in reducing the vascular permeability response to mast cell degranulation than to histamine. 5 In conclusion, the vasodilator response to histamine is mediated by both H1- and H2-receptors; the permeability response to histamine is mediated solely by H1-receptors. A combination of H1- and H2-receptor antagonists appears to be more effective than either antagonist alone in reducing cutaneous inflammatory reactions involving histamine.     

Involvement of histamine H1- and H2-receptors in induced asthmas in dogs.

Participation of histamine H1- and H2-receptors in both asthmas, i.e. experimentally induced bronchoconstriction and bronchosecretion, with ascaris suum and histamine in anesthetized dogs was investigated. Dogs given 0.2% histamine solution or ascaris antigen (3 mg protein) by inhalation showed increases in respiratory resistance (Rrs) and respiratory rate to 2.5-5.0 fold. Airway secretion volume was also significantly increased 3-4 fold. The increase in Rrs by histamine inhalation was effectively inhibited or abolished by a histamine H1-receptor antagonist, chlorpheniramine (0.3-1 mg/kg i.v.), but not by a H2-receptor antagonist, cimetidine (1-3 mg/kg i.v.). The increase in Rrs by antigen inhalation was reduced by relatively high doses of chlorpheniramine (1-3 mg/kg i.v.), and not by cimetidine. In contrast, hypersecretion of tracheobronchial fluid in both asthmas was significantly prevented by either chlorpheniramine or cimetidine. Combinations of both antagonists abolished the hypersecretion. Atropine (2 mg/kg i.v.) significantly inhibited the occurrence of responses in both asthmas. The results suggest that histamine is involved in the allergic asthma produced by ascaris suum and that histamine directly evokes airway constriction through H1-receptors and hypersecretion of tracheobronchial fluid through H1- and H2-receptors, and, in part, indirectly activates the cholinergic pathway.     

Effects of TAK-427 on acute nasal symptoms and nasal obstruction in guinea pig model of experimental allergic rhinitis

TAK-427 (2-[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate) is a novel anti-allergic agent that has both histamine H1-receptor antagonist and anti-inflammatory activities. In this study, we evaluated the efficacy of TAK-427 on acute nasal responses and nasal obstruction using various guinea pig models of allergic rhinitis. TAK-427 inhibited the histamine-induced nasal reactions with an ID50 value of 0.633 mg/kg, p.o. TAK-427 (0.1-10 mg/kg, p.o.) and most histamine H1-receptor antagonists tested inhibited the increase in intranasal pressure, nasal hypersecretion, sneezing and nasal itching caused by a single antigen challenge in sensitized guinea pigs. In addition, TAK-427 (0.3, 30 mg/kg, p.o.) significantly inhibited the development of nasal obstruction when sensitized guinea pigs were repeatedly challenged via inhalation with Japanese cedar pollen, whereas the histamine H1-receptor antagonist, azelastine (1 mg/kg, p.o.), and ketotifen (1 mg/kg, p.o.) were without effect. These results suggest that TAK-427 might not only suppress acute nasal symptoms but also ameliorate nasal obstruction via the effects other than those as a histamine H1-receptor antagonist.     

Histamine receptor type coupled to nitric oxide-induced relaxation of guinea-pig nasal mucosa

1 The aim of this study was to characterize the histamine receptor type mediating relaxation of the vascular bed of the nasal mucosa from the guinea-pig, and to determine the role of cyclo-oxygenase products and nitric oxide in this relaxant response to histamine. These studies were performed in isolated nasal mucosae examined in vitro to obtain potencies of histamine receptor-type selective agonists in causing vasorelaxation and to determine affinities of histamine receptor antagonists for inhibiting histamine-induced relaxation. 2 After contraction of nasal mucosae with noradrenaline, histamine caused a maximal relaxation response that was 75 +/- 6% of the contraction caused by noradrenaline with a mean EC50 value of 4.3 +/- 0.5 microM. Neither dimaprit (H2-receptor selective) nor R-alpha-methylhistamine (H3-receptor selective) caused significant relaxation of nasal mucosae. In contrast, betahistine (H1-receptor selective) caused an 81 +/- 7% relaxation of noradrenaline-induced tone with an EC50 value of 15 +/- 1 microM. 3 pA2 experiments were performed to obtain KB values of chlorpheniramine (H1-receptor selective) and diphenhydramine (H1-receptor selective) for blocking histamine-stimulated relaxation of nasal mucosae. KB values for chlorpheniramine (0.87 nM) and diphenhydramine (7.4 nM) were consistent with their interaction at the H1-receptor type. Additionally, neither 10 microM cimetidine (H2-receptor selective) nor 1 microM thioperamide (H3-receptor selective) had any effect on the relaxation curve for histamine. 4 In the presence of 10 microM indomethacin (cyclo-oxygenase inhibitor), histamine caused a maximal relaxation response of 73 +/- 5% of the noradrenaline-induced tone with an EC50 value of 2.9 +/- 0.2 microM, which was not different from control values (EC50 = 5.0 +/- 0.4 microM; maximal relaxation = 71 +/- 6%). In contrast, 200 microM NG-nitro-L-arginine (nitric oxide synthase inhibitor) completely inhibited histamine-induced relaxation of nasal mucosae. 5 In conclusion, data from the present study suggest only the H1-receptor type mediates relaxation of nasal mucosal blood vessels to histamine, and histamine-induced relaxation of nasal mucosae is entirely dependent on nitric oxide production.     

Phencyclidine blocks histamine H3-receptors in rat brain

Phencyclidine (PCP) was examined for its ability to modulate histamine release from rat brain slices labeled with L-[3H]histidine. PCP failed to mimic but completely reversed the autoinhibitory effect of histamine at H3-receptors with an apparent Ki value of 13 +/- 3 microM. A direct interaction of PCP with H3-autoreceptors rather than PCP or sigma receptor sites was confirmed by binding studies. PCP inhibited the binding of [3H](R)alpha-methylhistamine to H3-receptor sites in rat cerebral membranes with a Ki value of 25 +/- 2 microM. It is concluded that PCP is a H3-receptor antagonist of moderate potency.     

Increase of plasma renin activity after subcutaneous application of compound 48/80 in the rat

Subcutaneous (s.c.) administration of compound 48/80 (3.0 mg/kg) to conscious rats produced a time-dependent long-lasting increase of plasma renin activity (PRA). A dose-related increase of the hematocrit was also observed after injection of compound 48/80. The onset of the hematocrit increase preceded that of PRA increase. Pretreatment with a dose of more than 20 mg/kg of histamine H1-receptor antagonists such as tripelennamine or diphenhydramine prior to the injection of compound 48/80 (3.0 mg/kg s.c.) attenuated or abolished the effects of compound 48/80 on PRA, hematocrit and plasma extravasation. Pretreatment with cimetidine (histamine H2-receptor antagonist, 40 mg/kg i.p.) had no effect on these plasma variables. The increase of PRA caused by s.c. administration of compound 48/80 was not affected by the pretreatment with propranolol (beta-adrenoceptor antagonist, 10 mg/kg i.p.), which completely inhibited the isoproterenol (0.5 mg/kg s.c.)-induced PRA increase. Administration of compound 48/80 did not induce a significant PRA increase in the nephrectomized rats although the increase of hematocrit following s.c. administration of compound 48/80 persisted despite the absence of kidneys. S.c. administration of compound 48/80 (3.0 mg/kg) led to a significant decrease of histamine content at the site of injection and to a significant increase in plasma histamine concentration without affecting arterial blood pressure. The present data suggest that s.c. administration of compound 48/80 stimulates the release of histamine from cutaneous mast cells, which cause an increase in vascular permeability to plasma protein via the stimulation of histamine H1-receptors, then leads to hypovolemia. The resulting hypovolemia may directly stimulate the juxtraglomerular cells of the kidney to release renin.     

Effect of ketotifen on acute gastric lesions and gastric secretion in rats.

Ketotifen, a histamine H1-receptor antagonist and mast cell stabilizer, significantly protected the rat gastric mucosa against lesions induced by necrotizing agents, histamine or compound 48/80. The agent significantly inhibited the basal gastric acid secretion, but had little or no effect on the histamine-stimulated secretion. The mucosal protective effect was observed even at a dose that had little or no effect on gastric acid secretion, suggesting that ketotifen exhibits so-called cytoprotective activity.     

Acetylcholine mediation of the contractile response to histamine in human bladder detrusor muscle

In Krebs solution, histamine evokes in human bladder detrusor muscle strips a dose-dependent contractile response which consists of two pharmacologically distinct responses: a high-sensitivity response evoked at 0.4-2 microM histamine, which is potentiated by neostigmine (0.1 microM) or blocked by atropine (0.1 microM) or ranitidine (1 microM); a low-sensitivity response evoked at 4-40 microM histamine and blocked by dimethindene or diphenhydramine. These findings suggest that the contractile response to low doses of histamine is mediated by acetylcholine released from a site proximal to the muscle. This effect of histamine seems to be mediated by a site which is insensitive to the H1 antagonists dimethindene and diphenhydramine but blocked by the H2 antagonist ranitidine.     

Central hypertensive action of histamine in conscious normotensive cats.

In conscious normotensive cats intraventricular (i.c.v.) administration of histamine (2.0-50.0 mug) induced dose-related rises in blood pressure, with no increase in heart rate. The hypertensive response elicited by a sub-maximal dose of histamine (10.0 mu i.c.v.) was significantly antagonised by central pretreatment with the H1-receptor antagonist mepyramine maleate (200 mug i.c.v.) but not by the H2-receptor antagonist metiamide hydrochloride (1.0 mg i.c.v.). Behavioural responses were obtained in response to to histamine (10.0 and 50.0 mug i.c.v.), which were not antagonised by these antihistamine pretreatments.     

The effects of H2-receptor antagonists on anaphylaxis in the guinea-pig.

Histamine has been shown to inhibit a variety of immune responses including the antigen-induced, IgE mediated, release of histamine from sensitized human leucocytes and from sensitized monkey and dog mast cells. The inhibitory action of histamine appears to be mediated by action at a histamine H2-receptor. In in vitro experiments the H2-receptor antagonist metiamide has been shown to block this histamine effect and it has been suggested that H2-receptor antagonists could intensify immediate hypersensitivity reactions in vivo. The effects of the H2-receptor antagonist metiamide and cimetidine have been studied in in vitro and in vivo models of anaphylaxis in the guinea-pig. The amount of extracellular histamine found after antigen challenge is greater when an H2-receptor antagonist is present during the incubation of mast cells with antigen. Bronchoconstriction induced by antigen in sensitized guinea-pig is exacerbated only by high doses of cimetidine. Possible explanations for the mechanism of action involved are discussed.