Histamine Solution Research Articles

Nasal histamine challenges in symptomatic allergic rhinitis

Twenty subjects (seven with perennial allergic rhinitis, seven with symptomatic seasonal allergic rhinitis, and six normal control subjects) underwent assessment of nasal sensitivity to histamine. Nasal resistance was measured by posterior rhinometry under control conditions and after log incremental doses of histamine solution pipetted into the nose (0.5 to 5000 μg). Allergic subjects exhibited a twofold rise of nasal resistance with doses of 0.5, 5, or 50 μg of histamine, whereas the nasal resistance in normal subjects remained unchanged until 500 or 5000 μg of histamine had been administered. Nasal reactivity to histamine was not correlated with symptoms on the day of testing but was correlated with the number of positive wheals to skin prick testing. It was concluded that nasal resistance is more sensitive to histamine in subjects with allergic rhinitis than in normal control subjects and that this difference may be used as the basis of a diagnostic test.

Bronchodilator Efficacy of Liposome Formulations of Metaproterenol Sulfate in the Anesthetized Guinea Pig

AbstractExperiments were performed in anesthetized guinea pigs to determine the effects of encapsulation of the beta-2 adrenergic agonist drug metaproterenol sulfate (MPS) into various liposomes. Bronchodilator activity was measured as the ability of inhaled aerosolized MPS to reduce the bronchoconstriction resulting from repeated administration of inhaled aerosolized histamine solution. One percent MPS in saline (free MPS) reduced the airway resistance response to the inhaled histamine challenges. This bronchodilator effect returned toward control over the 2 hr study period, and had returned to control values 10-12 hr after drug administration. In addition, the free MPS caused significant tachycardia and systemic vasodilation. All three liposome-encapsulated MPS formulations caused significantly smaller cardiovascular side effects. One formation also showed immediate inhibition of the histamine bronchoconstriction similar to free drug. This effect persisted until the 10-12 hr study period, which suggests...

Increased bronchial responsiveness to histamine associated with shortened inhalation time

A study was undertaken to assess the variability of results of histamine inhalation tests with the tidal breathing method, keeping the total dose of histamine delivered to the mouth constant but using either different nebulizers or the same Wright nebulizer operated under changing conditions. Seventeen asthmatic children had double histamine bronchial provocation tests with a Bennett-Twin nebulizer (output 0.31 ml/min, nebulization time 1 min) and a Wright nebulizer (output 0.15 ml/min, nebulization time 2 min), with a driving flow rate, in both instances, of 7 L/min. Another group of 15 asthmatic children had double provocation tests with a Wright nebulizer driven by a flow rate of either 7 L/min (output 0.15 ml/min, nebulization time 2 min) or 12 L/min (output 0.30 ml/min, nebulization time 1 min). In each experiment the volume of histamine solution delivered was about 0.30 ml. PC20-FEV1 was significantly lower, indicating an increased bronchial response, when both methods using "faster" delivery of histamine were used. We conclude that comparison of results obtained with histamine inhalation tests by the tidal breathing method cannot be made unless the nebulizer and operating criteria are the same.

Investigation of the effects of histamine inhalation on the tracheobronchial tree of calves by the forced oscillation technique.

Effects of histamine inhalation were investigated with two different techniques in nine conscious, healthy calves. The oesophageal balloon technique was used to measure the dynamic respiratory compliance (Cdyn) and the pulmonary resistance (RL). The reactance (Xrs) and the resistance (Rrs) of the respiratory system were measured at high frequencies by the forced oscillation technique. These parameters were recorded before and after histamine inhalation. Three histamine dihydrochloride solution concentrations were used (16 mg/ml; 32 mg/ml; 64 mg/ml). Histamine inhalation induced a decrease in Cdyn and Xrs an increase in Rrs, RL and of the resonant frequency and a negative frequency dependence of Rrs. Some of these changes were satisfactorily correlated with the histamine solution concentrations. The resonant frequency was well correlated with Cdyn. It was concluded that histamine inhalation induces a decrease of the calibre of small and large airways and a non-homogeneous behaviour of the pulmonary ventilation in awake calves. The forced oscillation technique can be used to perform an inhalation provocation test in unsedated animals.

Hypoxia-induced enhancement of nonspecific bronchial reactivity: role of leukotrienes.

Because alveolar hypoxia has been shown to cause an increase of leukotrienes in lung lavage fluid, we tested the hypothesis that enhancement of nonspecific bronchial reactivity during alveolar hypoxia may be mediated by leukotrienes. In nine conscious sheep we determined specific lung resistance (sRL) before and after exposure to either air or a hypoxic gas mixture (13% O2) for 30 min. The sheep then inhaled 50 breaths of aerosolized 5% histamine solution (n = 6) or 10 breaths of 2.5% carbachol solution (n = 6) on different days, and the measurements of sRL were repeated. On subsequent days the above protocols were repeated after pretreatment with aerosolized FPL 57231 (3 ml, 1% solution), a leukotriene receptor antagonist. Inhalation of histamine and carbachol after exposure to air caused an increase in mean sRL to 337 and 342% of base line, respectively (P less than 0.05). Exposure to the hypoxic gas mixture had no effect on sRL but enhanced the histamine- and carbachol-induced increases in mean sRL to 621 and 646% of base line, respectively (P less than 0.05); these increases were significantly higher than those observed after air exposure (P less than 0.05). FPL 57231 prevented the hypoxia-induced enhancement of bronchial reactivity to histamine and carbachol without affecting the airway responsiveness to these agents after air. In another group of eight sheep, aerosolized leukotriene C4, at a dose (50 micrograms) that per se had no affect on sRL, enhanced the bronchial reactivity to carbachol. These data suggest that in sheep during alveolar hypoxia airway hyperresponsiveness may be due to the priming of airway smooth muscle by leukotrienes.

Histamine and allergen induced changes in nasal airways resistance measured by anterior rhinomanometry: reproducibility of the technique and the effect of topically administered antihistaminic and anti‐ allergic drugs.

1. Changes in nasal airways resistance (NAR) following the topical application of histamine and allergen solutions were measured by passive anterior rhinomanometry. 2. The repeatability of five consecutive measurements of resting NAR prior to provocation with histamine or allergen (expressed as the coefficient of variation) was 32.8% and following instillation of saline control solution 37.2%. 3. The repeatability of five consecutive measurements of NAR during the nasal obstruction produced by histamine and allergen was similar to that recorded prior to provocation; the coefficients of variation (median values) being 39.6% and 33.1% respectively. The degree of variability was not related to the dose of agonist or the degree of nasal obstruction. 4. The reproducibility of histamine or allergen induced changes in NAR on four separate weekly occasions showed no significant intra-subject differences. 5. The effects of sodium cromoglycate (SCG), clemastine and ketotifen administered to the nasal mucosa 30 min before provocation with histamine and allergen were compared in a random order, double-blind, placebo controlled study. 6. Clemastine and SCG, but not ketotifen, significantly inhibited the nasal response to increasing concentrations of histamine. None of the drugs administered in the concentrations used in this study significantly inhibited the nasal response to allergen.

Long-term stability study of histamine in sterile bronchoprovocation solutions

The long-term stability of histamine in sterile bronchoprovocation solutions stored under different conditions was studied. Histamine solutions (2 and 8 mg/mL) were stored in specially adapted translucent and black plastic bottles and kept in a cool place (12 degrees C) and exposed to fluorescent light (500 foot-candles intensity). Multiple aliquots of each concentration were also stored at -20 degrees C in 12 X 75 mm sterile polypropylene tubes with snap caps and covered with aluminum foil. The content of histamine in the stored samples was determined by a stability-indicating colorimetric assay. The histamine solutions were stable for up to eight months at 12 degrees C when stored in either of the specially adapted translucent or black plastic bottles, irrespective of normal long-term exposure to fluorescent light. No important changes were observed in the histamine concentration when these solutions were stored at -20 degrees C in polypropylene tubes for up to a year. Histamine solutions used in bronchoprovocation tests can be stored in plastic bottles in a cool place or in the refrigerator. It is not necessary to protect these solutions from normal long-term exposures to fluorescent light to ensure clinically acceptable stability.

Attenuation of tracheal smooth muscle contraction by connective tissue

Removing the fibroelastic connective tissue, which surrounds the smooth muscle of the pig trachea, enhanced contractions and decreased desensitization in vitro in response to histamine. There were no differences between the preparations in the presence of indomethacin. The magnitude of contraction to acetylcholine was not significantly different. Incubation of the connective tissue in histamine solution caused the appearance of a substance(s) which relaxed other, precontracted tracheal muscles. Propranolol did not block this relaxation. Intact connective tissue appears to reduce the reactivity of the tracheal smooth muscle to histamine.

Separate effects of topical indomethacin on the itch response and on the flare reaction induced by histamine in human skin

The effects of topical indomethacin on histamine responses and histamine release were studied in 15 healthy volunteers. Three hours before testing, the indomethacin solution was applied under occlusion on one arm and the corresponding vehicle on the other. Solutions of histamine and the histamine releasing compound 48/80 were injected intradermally in both arms. Indomethacin treatment inhibited the flare reactions induced by histamine and compound 48/80 to about 50%, whereas no influence was seen on the itch responses. Our results indicate that indomethacin has no effect on the release of histamine, but it selectively suppresses the histamine-induced flare reaction leaving the itch duration unaffected.

Simple stability-indicating assay for histamine solutions

A chemical stability-indicating assay for the routine analysis of histamine in isotonic-phosphate buffer solutions was developed and evaluated. A quantitative colorimetric assay was developed by adapting the Pauly reaction specific for the imidazole group for the determination of histamine in buffer solutions. Stock solutions of histamine diphosphate 1 mg/mL were diluted with isotonic phosphate buffer to produce standards for an imidazole-group assay and for the USP assay method based on the Folin reaction of free amino groups. The specificity of the assays was evaluated by subjecting samples to ultraviolet irradiation and heat for various time periods and then analyzing for histamine content. Both of the colorimetric assays provided reproducible linear calibration curves passing through the origin for histamine diphosphate concentrations. For the Pauly-reaction assay, the average coefficients of variation between and within runs were 0.5% and 0.1%, respectively. The assay had recoveries of 100.6% and 100.8% at 8 and 25 micrograms/mL of histamine diphosphate concentrations, respectively, and a sensitivity of 3 micrograms/mL. Based on the results of the Pauly-reaction assay, irradiation caused decreases in the apparent concentrations as large as 69.2% depending on the duration of the irradiation and distance from the light source. When the histamine diphosphate solutions were stored in the dark at 60 degrees C for five days, a decrease of only 6.3% occurred. Based on the results of the Folin-reaction assay, irradiation caused increases in the apparent concentrations as large as 50.6%. The Pauly colorimetric assay based on the imidazole group appears to be more appropriate for histamine solutions than the amino-group assay based on the Folin reaction.

Radiolysis of aqueous and aqueous‐ethanolic solutions of histamine

AbstractAqueous solutions of histamine and imidazole were gamma‐irradiated in the absence and presence of ethanol. The protective effect of ethanol on the radiation cleavage of the imidazole ring depends on the pH of irradiated solutions: at neutral pH the presence of ethanol decreases radiation degradation of imidazole skeleton whereas at acidic pH it does not play any protective role. On the contrary in irradiated aqueous‐ethanolic solutions of histamine 2 HCl (pH 4.5) some additional reactions between histamine and products of radiolysis of ethanol, mainly with acetaldehyde, take place leading to the increase of total radiation loss of histamine and to the formation of further radiation products. Similar products were also found in 3H preparations of histamine stored in aqueous‐ethanolic solutions. Possible mechanisms of radiation degradation of histamine were discussed.

Effect of aerosol histamine on lung lymph in awake sheep.

This study examined the effect of aerosol histamine on lung lymph in the awake sheep. Eleven sheep were chronically instrumented for measurement of lung lymph, lung mechanics, and vascular pressures. Aerosol histamine was given by use of a Collison nebulizer and delivered via a tracheostomy tube. Five breaths of a 30 mg/ml histamine solution caused lung lymph flow (QL) to increase from a base line of 5.5 +/- 0.5 (SE) ml/h to 14.3 +/- 1.5 (P less than 0.05) and the lymph-to-plasma protein concentration ratio (L/P) to increase from 0.63 +/- 0.02 to 0.72 +/- 0.02 (P less than 0.05). The concentration of aerosol histamine required to change QL by 30% (ED130QL) was determined by giving increasing concentrations of aerosol histamine every 15 min. The mean ED130QL was 22.2 mg/ml. The dose of histamine required to increase QL by 30% did not correlate (r = 0.04, n = 7) with the dose required to decrease dynamic compliance by 35%. The increase in QL lasted 100 +/- 19 min. Hourly exposure to five breaths of 30 mg/ml for 5 h caused a sustained increase in QL in two sheep and a waning effect in two sheep. The combination of aerosol histamine and elevated microvascular pressure (achieved by inflating a Foley catheter situated in the left atrium) caused changes in QL and L/P not totally consistent with the hypothesis that histamine increased pulmonary vascular permeability. Increased vascular permeability in the bronchial circulation was considered a likely explanation of the data.

Ocular disposition of topically applied histamine, cimetidine, and pyrilamine in the albino rabbit.

Aqueous solutions of pyrilamine, cimetidine, and histamine were instilled into the eyes of albino rabbits and drug levels determined as a function of time in the cornea, conjunctiva, aqueous humor, and iris-ciliary body. For all three drugs, less than 1% of the applied dose penetrates to the aqueous humor. Moreover, cimetidine and histamine are significantly less bioavailable than pyrilamine. Both cimetidine and histamine appear to bind to precorneal mucin and thus exhibit binding to conjunctival tissue with subsequent low penetration into the cornea and prolonged peak times in the aqueous humor. In addition, both drugs show binding to the iris-ciliary body as well. The influence of solution pH on the penetration of these compounds was also investigated, and a factor of two increase in aqueous levels was noted for the pH range 5-8, which encompasses the pKa's for these compounds.

Functional depression of H 2 histamine receptors in sheep with experimental allergic asthma

We tested the hypothesis that airway hyperresponsiveness to histamine in the allergic sheep is related to functional depression of H 2 histamine receptors. Thirteen of 32 sheep responded with bronchoconstriction to inhaled Ascaris suum antigen (allergic sheep), and the remainder served as controls (nonallergic sheep). In the allergic sheep, 50 and 100 breaths of 5% histamine solution increased mean pulmonary resistance (R L) to 235% and 438% of baselines, respectively. The corresponding values in nonallergic sheep were 200% and 211%, indicating a greater response to the higher dose of histamine in allergic sheep. Selective H 1-receptor stimulation with 50 breaths of histamine (pretreatment with the H 2 -receptor antagonist metiamide) failed to enhance the effect of histamine in allergic sheep (mean R L increased to 239% of baseline) whereas it enhanced the histamine response in nonallergic sheep (R L increased to 438% of baseline). Selective H 2 -receptor stimulation (pretreatment with the H 1-receptor antagonist chlorpheniramine) caused histamine to decrease R L by 31% in the nonallergic sheep group; it blocked but did not reverse the histamine effect in the allergic sheep. Similar observations were made in a different group of animals when selective H 1- or selective H 2 -receptor stimulation was produced by 100 breaths of histamine. The cutaneous wheal response to intradermal histamine dilutions of 0.0001, 0.001, 0.01, and 1 mg/ml was similar in both groups. In nonallergic sheep, both chlorpheniramine and metiamide blunted the cutaneous wheal response. In allergic animals, only chlorpheniramine blunted the cutaneous wheal response, whereas metiamide was without effect. We conclude that airway hyperresponsiveness to histamine in allergic sheep is related to a functional depression of H 2 receptors and that such a defect is observed both in the airways as well as in the skin.

Modification of airway histamine-receptor function with methylprednisolone succinate

The purpose of the present study was to investigate whether glucocorticosteroids alter airway histamine-receptor function. We measured pulmonary resistance in six conscious sheep before and after inhalation challenge with 100 breaths of 5% histamine solution, without and with intravenous pretreatment with the specific H 1 - and H 2 -receptor antagonists. Inhalation of histamine (combined H 1 and H 2 stimulation) increased mean pulmonary resistance (R L) to 290% of baseline (p < 0.05). Pretreatment with the H 2 antagonist, metiamide (selective H 1 stimulation), enhanced the effect of histamine, with a mean R L increase to 760% of baseline (p < 0.05). Histamine challenge after pretreatment with the H 1 antagonist, chlorpheniramine (selective H 2 stimulation), decreased R L to 40% of chlorpheniramine value (p < 0.05). A single intravenous bolus injection of methylprednisolone succinate (30 mg/kg) 30 min before histamine challenge suppressed the airway responsiveness to histamine. with a mean R L increase to only 186% of baseline. After methylprednisolone, selective H 1 -receptor stimulation with histamine elicited a blunted H 1 -receptor response; mean R L increased to only 248% of baseline. Both changes were significantly lower than that with histamine alone (p < 0.05). Methylprednisolone per se blunted the chlorpheniramine-induced increase in R L, which made it difficult to evaluate H 2 -receptor function (R L decreased to 67% of postchlorpheniramine value). However, in the presence of increased airway tone with carbachol, selective H 2 stimulation with histamine decreased R L to 26% of postcarbachol value (p < 0.05), thus excluding suppression of H 2 receptors. Methylprednisolone had no effect on carbachol-induced increase in R L. In conscious sheep, methylprednisolone blunts airway responsiveness to histamine by suppressing H 1 receptors without significantly altering H 2 receptors or cholinergic-receptor function.

Local intranasal immunotherapy for grass-allergic rhinitis

In a double-blind controlled study, local intranasal immunotherapy was evaluated for the treatment of grass pollenosis. On the basis of serum grass-specific IgE levels, 50 grass-allergic patients were randomly divided into three groups and treated with either an aqueous solution of mixed-grass extract, a formaldehyde-modified mixed-grass extract (allergoid), or a histamine solution (placebo). Intranasal solutions were administered in gradually increasing doses over a preseasonal 10 wk period, Ad' verse local reactions from the aqueous grass extract were frequent during treatment. Few adverse reactions occurred from the allergoid or histamine solutions. During the pollen season, patients receiving both grass extracts had much lower symptom/medication scores than patients receiving placebo. The severity of eye symptoms was the same in all groups. After treatment, serum grass-specific IgE rose in patients receiving aqueous and allergoid extract; no change was noted in patients receiving placebo therapy. Grass nasal secretory-specific IgA titers in each group did not change during the study. The results of this study suggest that local intranasal immunotherapy with either aqueous or allergoid grass extracts is clinically effective for the treatment of grass pollenosis. Adverse reactions associated with the aqueous extract may limit its usefulness. No correlation was present between the secretory immune response and clinical benefit.

Histamine release into tracheal lumen and bronchial reactivity. Effect of local histamine administration on histamine release and bronchial reactivity.

The influence of tracheal lavage with histamine, and of i.v. administration of histamine on bronchospastic response was studied in 16 dogs. Airway response to acetylcholine inhalation was significantly increased after tracheal lavage with high concentrated histamine solution (1%). No influence on airway response was found after (1) tracheal lavage with lower concentrations of histamine and (2) its i.v. administration. The clinical importance of these manifestations is discussed.

Fetal and neonatal rat intestinal capillaries: permeability to carbon, ferritin, hemoglobin, and myoglobin.

The function of the mural components involved in vascular exchange (pinocytotic vesicles, fenestrations, intercellular junctions, and the basal lamina) was assessed by intravascular injection of tracers (carbon, carbon plus histamine, ferritin, hemoglobin, and myoglobin) on separate gestational days in fetal and neonatal rat intestinal capillaries. The continuous capillaries present through day 17 of gestation were impermeable, even at junctions, to all the tracers within the maximum circulation time studied (3 minutes). Most of the luminal pinocytotic vesicles were labeled within 3 minutes with myoglobin (3.3-nm diameter) or hemoglobin (5.5-nm diameter), while only occasional vesicles contained ferritin (11-nm diameter) and none contained carbon (25-50nm diameter). Even though luminal pinocytotic vesicles contained the smaller tracers, no vesicular transport and discharge were ever seen. The fenestrated vessels present from day 18 of gestation allowed a rapid extravasation of ferritin and hemoglobin via diaphragmed fenestrations. At no time period did extravasation of carbon take place, nor did the carbon plus histamine solution induce vascular leakage. Once a tracer gained access to the extravascular space, the developing basal lamina did not seem to retard its movement.

The modification by ketotifen of respiratory responses to histamine and antigen in guinea-pigs.

Aerosolized solutions of histamine or ovalbumin were administered to control or ovalbumin-sensitized guinea-pigs. The time to onset of respiratory distress (preconvulsion time) during challenge with these agents was measured using a force-displacement transducer on the animal's back. The preconvulsion time for each guinea-pig was compared with and without ketotifen pretreatment. Ketotifen administered both by aerosol and intraperitoneal injection (i.p.) significantly protected (p less than 0.001) each guinea-pig from the effects of aerosol challenge with histamine. Ovalbumin-sensitized animals were also protected from the effects of antigen aerosol challenge by ketotifen pretreatment. Sodium cromoglycate (DSCG), administered as an aerosol, did not protect sensitized animals from ovalbumin challenge. The Konzett-Rössler technique was used to measure the response to the intravenous injection (i.v.) of histamine in anaesthetized artificially ventilated guinea-pigs. Ketotifen was three times more potent than mepyramine in inhibiting the histamine-induced increase in air overflow volume.

Significance of sustained gastric hypersecretion by the emulsified histamine solution.

Experimental production of gastric and duodenal ulcers was investigated in dogs by administration of histamine emulsified in Freund's incomplete adjuvant. Acid secretory responses were also checked. The results are as follows: Intramuscular administration of 10 mg/day of the emulsified histamine solution caused sustained gastric hypersecretion due to gradual liberation of histamine but produced no apparent side effects. However, neither gastric nor duodenal ulcer was observed within 2 months with the dosage of 10 mg/day. These results suggest that intramuscular administration of the dosage of 10 mg/day within 2 months would be a valuable means to elucidate the pathogenesis of ulcer under the sustained gastric hypersecretion.