Elevated Histamine Levels Research Articles

Mucosal histamine content and histamine secretion in Crohn's disease, ulcerative colitis and allergic enteropathy.

Histamine exhibits various biological effects in inflammatory and immunological reactions. To further define its potential role in allergic enteropathy and inflammatory bowel disease, both gut mucosal histamine levels and histamine release from endoscopic biopsy samples were measured. Tissue histamine content resulted from addition of the released amount of histamine and the remaining part of tissue histamine. The results demonstrate highly elevated mucosal histamine levels of the large intestine in allergic enteropathy. In inflammatory bowel disease histamine content and secretion were found to be significantly increased particularly in affected mucosa of Crohn's disease and ulcerative colitis than in unaffected tissue or in healthy controls. These findings give strong evidence that mast cell mediators like histamine play a role in the pathogenesis of these diseases. Mucosal histamine is thus concluded to contribute to the immuno-inflammatory reactions of the intestine found in these disease states and to reflect the degree of colonic inflammation in Crohn's disease and ulcerative colitis.

Amperometric detection of histamine at a quinoprotein dehydrogenase enzyme electrode

Methylamine dehydrogenase, a tryptophan tryptophyl quinone (TTQ) containing quinoprotein, catalyzes the oxidation of a variety of primary aliphatic monoamines and diamines to their respectives aldehydes and ammonia. This paper reports the construction and characterization of an enzyme electrode capable of detecting histamine and methylamine at +200 mV versus a saturated calomel reference electrode. The methylamine dehydrogenase isolated from Paracoccus denitrificans was used in conjunction with the insoluble mediator tetracyanoquinodimethane (TCNQ) to construct enzyme electrodes which will potentially provide simple rapid analysis of histamine without the need for the extensive sample pretreatments currently required in HPLC and GLC analysis. The linear response of this amperometric sensor, between 0 and 200 μM, correlates well with elevated histamine levels predominant in patients with chronic myelogenous leukaemia, whilst the observed limit of detection, 4·8 μM, compares favourably with the lower limits of detection reported for a potentiometric histamine sensitive enzyme electrode.

Aerosolized acetaldehyde, but not ethanol, induces histamine-mediated bronchoconstriction in guinea-pigs.

It was reported that ethanol-induced bronchoconstriction was associated with elevated serum levels of acetaldehyde and histamine in Japanese asthmatic patients, but there is no study to investigate the airway response to acetaldehyde. We performed this animal study to test the hypothesis that acetaldehyde has the bronchospastic action via histamine release. First, we investigated the airway response to ascending doses (31.3, 62.5, 125, and 250 mM) of inhaled ethanol or acetaldehyde in guinea-pigs. Secondly, guinea-pigs pretreated with intraperitoneal injection of saline or 20 mg/kg diphenhydramine inhaled acetaldehyde. Finally, guinea-pigs pretreated with intraperitoneal injection of saline or 0.5 mg/kg atropine sulfate inhaled acetaldehyde. Inhalation of acetaldehyde, but not ethanol, caused bronchoconstriction in a dose-dependent manner. The bronchoconstriction induced by inhaled acetaldehyde was completely prevented by pretreatment with diphenhydramine. Atropine had no preventing effect against the acetaldehyde-induced bronchoconstriction. In conclusion, acetaldehyde has the bronchospastic action via histamine release in guinea-pigs. It is suggested that histamine H1-antagonists may be available for preventing alcohol-induced asthma.

Asthma ‘Of Mice and Men’–How do animal models help us understand human asthma?

Asthma ‘Of Mice and Men’–How do animal models help us understand human asthma?

The clinical and biological signs of histamine release during induction of anaesthesia and preparation of the surgical patient: A farewell party for the classical manifestations of anaphylaxis

The clinical manifestations of histamine release and their clinical relevance are still matter of considerable debate among anaesthesiologists whereas surgeons have no opinion at all. In a series of six clinical-experimental trials a gold standard for histamine release was established, the term “histamine release reaction” was determined, and a combination of clinical predictors was created for assessing the effectiveness of a prophylaxis with histamine H1+H2-antagonists. After the construction of the gold standard “elevated plasma histamine”, in the first three trials the experimental validation, the selection of standard variables for a clinical test and the validation with authentic histamine was accomplished. In three further trials this test was applied to several histamine releasers which have been commonly used for induction of anaesthesia and preparation of a surgical patient, namely, the hypnotic propanidid, the muscle relaxant atracurium, and the plasma substitute Haemaccel. In these trials, H1+H2-sensitive variables were also selected for a diagnostic classification of histamine release reactions. Trial 1 demonstrated that elevated plasma histamine levels indicated histamine release with a high accuracy. Selection of variables after authentic histamine with and without H1+H2-antagonists chose the following clinical signs: cutaneous signs, tachycardia, and hypertension (trial 2). This test including the three variables, after injection of authentic histamine, showed a high accuracy (trial 3). However, when for each histamine releaser and H1+H2-sensitive combination of variables was assessed in trial 4–6, the results were very different in all the performance criteria (Table 6). Propanidid showed very bad results in accuracy which differed not at all from those of the prevalence (incidence) of adverse reactions (flipping a coin, no gain by diagnostic information). Atracurium was in-between, not very convincing with its gains, but Haemaccel was the best-however not for the classical signs of anaphylaxis. It is concluded-that the standard variables of histamine release, in combination with a broader spectrum of signs, can be used for diagnosing (classifying) the endpoint of a histamine release reaction. This definition is urgently needed for analysing the data of an extended randomized trial which used H1+H2-receptor antagonists for preventing adverse reactions in anaesthesia due to histamine release.

Elevated plasma histamine levels in trauma patients: Results of a well-designed cross-sectional study with polytrauma and two control groups

Several components of trauma (initial stressors, responses and burdens and therapeutic interventions) are able to induce histamine release, but our knowledge is very limited about the role of histamine in this fundamental scenario in human life. Previous studies suffer from unreliable histamine assays from biases in sample preparation and from confounding biases in the clinical setting. Hence a well-designed (6) crosssectional study was performed with polytrauma patients at the site of accident as a test group and two control groups in the hospital. The patients of the control groups suffered from single, peripheral trauma (more stress than injury) or being in the recovery period from single trauma and operation at day 5 (reconvalescence from traumatization).

Suction blister fluid histamine in fixed drug eruption.

The histamine concentration was measured from suction blister fluid obtained from normal and lesional skin of 8 patients with fixed drug eruption (FDE) caused by phenazone salicylate and from that of 2 healthy control subjects. In blister fluid samples obtained before peroral challenge with phenazone salicylate, the histamine concentrations were below 5 nmol/l both in uninvolved skin and in sites of previous FDE lesion (sample 0). After challenge, samples were taken from the incipient reaction that was visible after an average of 155 min. Histamine levels were significantly elevated in the blister fluid of 2 out of 8 FDE lesions (200 and 640 nmol/l) but in none of the uninvolved skin (sample 1). Two hours later (sample 2) the histamine levels were elevated in both uninvolved (mean 51.4 nmol/l) and lesional skin (mean 168 nmol/l). After 24 h (sample 3) the corresponding mean value was 25.4 nmol/l for uninvolved skin and 108 nmol/l for lesional skin. The histamine values in the blister fluid from FDE lesions in samples 2 and 3 were significantly higher (p less than 0.05) than those in the control blisters of uninvolved skin. An elevation of histamine levels comparable to that in the uninvolved skin of FDE patients was seen in the 2 healthy control subjects studied. The present study provides direct evidence of early release of histamine from mast cells or basophils in FDE and suggests that histamine is one of the mediators of clinical symptoms of FDE.

Circulatory depression and ventricular arrhythmias induced by compound 48/80 in anaesthetized rats

The effects of graded doses of compound 48/80 on various cardiovascular and respiratory parameters were studied in pentobarbitone-anaesthetized rats. Following intravenous injections, this compound significantly depressed the mean blood pressure (MBP), left ventricular pressure (LVP) and dLVP/dtmax, and caused ventricular tachycardia (VT) or fibrillation (VF) and death. Heart rate (HR) response were variable, and there were no marked changes in airway resistance or blood gases. Pretreatment of the animals with either cimetidine or diphenhydramine significantly prolonged the time of onset of VT/VF but failed to alter the changes in other circulatory variables. A combination of cimetidine and diphenhydramine significantly alleviated the decreases in MBP and LVP and prevented the occurrence of VT/VF. It is suggested that the circulatory depression and the occurrence of ventricular arrhythmias following the administration of compound 48/80 result from activation of H1- and H2-receptors by elevated blood histamine levels due to release of the amine from tissues.

Changes in the Metabolism of Histamine arid Monoamines After Occlusion of the Middle Cerebral Artery in Rats

Changes in the levels of histamine, monoamines, and their metabolites in the cerebral cortex and striatum after occlusion of the middle cerebral artery in rats were examined. The water content of the ipsilateral brain regions gradually increased after occlusion. In the ischemic side, 1 h after occlusion, the cortical norepinephrine and striatal 5-hydroxy-tryptamine levels significantly decreased, and striatal 3,4-dihydroxyphenylacetic acid and homovanillic acid levels markedly increased. In contrast, the levels of histamine and tele-methylhistamine in either brain region gradually increased and the changes became pronounced and statistically significant 6-12 h after induction of ischemia. The striatal histamine and tele-methylhistamine reached levels three- and twofold higher, respectively, than those of the contralateral side. In rats treated with alpha-fluoromethylhistidine 1 h before induction of ischemia, elevation of histamine and tele-methylhistamine was not observed. The elevated histamine level in the ipsilateral straitum at 9 h after occlusion was further significantly increased by the treatment with metoprine, an inhibitor of histamine-N-methyltransferase. These results suggest that the histaminergic activity in the brain is gradually enhanced by cerebral ischemia.

Elevated Bronchoalveolar Lavage Fluid Histamine Levels in Allergic Asthmatics Are Associated with Increased Airway Obstruction

Bronchoalveolar lavage (BAL) fluid was evaluated for histamine and tryptase levels in 61 samples (46 samples from 24 atopic asthmatics, seven samples from seven patients with allergic rhinitis, and eight samples from eight normal volunteers). Asthmatics and patients with allergic rhinitis had significantly higher BAL histamine than did normal subjects (169 +/- 22, 141 +/- 23, 42 +/- 6 pg/ml, respectively; p less than 0.05, both comparisons). BAL fluid tryptase levels were also higher in asthmatics and patients with allergic rhinitis than in normal subjects (0.36 +/- 0.03, 0.38 +/- 0.05, 0.23 +/- 0.04 ng/ml, respectively; p less than 0.05, both comparisons); however, levels of tryptase and histamine in BAL were not correlated (r = -0.03 in the group as a whole, r = -0.12 in the asthmatic group). BAL concentration of histamine correlated inversely with FEV1 percent predicted in the asthmatic group (r = -0.44, p less than 0.005). Asthmatics with high BAL fluid histamine (greater than or equal to 100 pg/ml, n = 23) had lower FEV1 percent predicted (80 +/- 3% versus 96 +/- 3%, p = 0.0005), lower FEV1/FVC ratio (72 +/- 1% versus 77 +/- 2%, p less than 0.05), higher percentage of BAL eosinophils (2.2 +/- 0.4% versus 0.6 +/- 0.1%, p less than 0.002), and greater airway responsiveness (lower PD20 [13.1 +/- 3.4 versus 41.5 +/- 13.7 cumulative breath units, p less than 0.05]) compared with asthmatics with low BAL fluid histamine (less than 100 pg/ml, n = 23).(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro andin vivo studies of radiographic contrast media-induced histamine release in pigs

Routine clinical use of radiographic contrast media (RCM) causes adverse reactions in some patients. To elucidate the mechanisms of these reactions both in vitro and in vivo studies are necessary. In this study, RCM-induced histamine release from isolated mast cells was compared with the in vivo release of histamine and cardiovascular symptoms using a porcine model. The 2 non-ionic preparations examined (Solutrast and Ultravist) released little or no histamine from the 4 cell types tested (porcine pulmonary, cardiac, hepatic, and renal mast cells). The 4 ionic preparations (Angiographin, Hexabrix Rayvist, and Telebrix) caused histamine release from most of the cell suspensions. In almost all cases, the cardiac mast cells were the most sensitive followed by the hepatic mast cells. All 4 RCM tested in vivo produced elevated plasma histamine levels in some animals. The highest incidence was observed using the ionic, high osmolal Rayvist (6 of 12 animals), followed by the non-ionic RCM with the lowest osmolality Ultravist (4 of 12 animals). In vivo, mechanisms in addition to direct histamine release may also be involved in RCM-induced adverse reactions, since low osmolal, non-ionic RCM can cause elevated plasma histamine levels without in vitro release. The susceptibility of cardiac mast cells to RCM-induced histamine release suggests that patients undergoing e.g. coronary angiography may be especially at risk for an adverse reaction.

Histamine release induced by opioid analgesics: A comparative study using porcine mast cells

Studies in vitro have demonstrated histamine release induced by opioid analgesics from rat peritoneal mast cells and human skin mast cells. In humans, elevated plasma histamine levels have also been found following intravenous or oral administration. This study compared the reactivity of five opioid analgesics on mast cell suspensions obtained from porcine heart, kidneys, liver and lungs. The five compounds investigated were hydromorphone, levomethadone, morphine, pethidine and oxycodone. Both morphine and hydromorphone produced little histamine release from all cell types tested. The other drugs demonstrated clear differences between the different cell populations. Thus, the cardiac cells responded most strongly to oxycodone but were the least responsive to pethidine. These differences, if confirmed in vivo, could indicate which drugs may be more suitable for patients with different underlying disease states.

Histamine, antihistamines and atopic eczema

Histamine is known to be a classical inducer of pruritus. In atopic eczema, itch is a prominent feature (regarded by some even as a 'primary lesion'!). One of the most potent chemical mediators of itch is histamine. Histamine, together with other mediators may play a role in the pathophysiology of atopic eczema: the increased release of histamine from basophil leucocytes of atopic patients has been described, as well as elevated histamine levels in plasma and skin during acute exacerbations of eczematous lesions. Therefore, application of H1 antagonists seems to be a rational regime in the symptomatic treatment of atopic eczema. Nevertheless, some controversy exists regarding the clinical efficacy of orally applied H1 antagonists in this disease, especially with regard to the newer non-sedating compounds such as terfenadine, astemizole, loratadine and cetirizine. Review of the literature shows that there are studies demonstrating a clear-cut antipruritic effect of non-sedating H1 antagonists. Thus the sedative action does not seem necessarily to be connected with therapeutic efficacy in treating itch in atopic eczema. Newer studies show that cetirizine exerts an additional inhibitory effect on eosinophils. This may broaden the therapeutic spectrum of this H1 antagonist in diseases with eosinophil involvement.

Inhibition of mediator release in systemic mastocytosis is associated with reversal of bone changes

A 59-year-old male presented with systemic mastocytosis with extensive skeletal involvement resulting in vertebral compression fractures and bone pain. Histomorphometric analysis of bone revealed increased mast cells, elevated static parameters of bone resorption, and low bone formation. Serum calcium, phosphorus, and alkaline phosphatase were normal; however, serum 1,25-dihydroxyvitamin D3 and osteocalcin levels were low. Histamine levels in plasma and urine were elevated. Following therapy with ketotifen, the patient had resolution of bone pain along with decreased flushing and pruritus. Elevated plasma and urine histamine levels normalized, as did 1,25-dihydroxyvitamin D3 and osteocalcin levels. Indices of low bone formation improved on therapy. Eroded surfaces improved but remained elevated. This case is the first demonstration that bone symptoms and histomorphometric change in systemic mastocytosis are reversed with inhibition of mast cell degranulation. The role of mast cells and their products in bone metabolism is poorly understood, but the therapy of bone disease in systemic mastocytosis should include inhibition of the release of mast cell products along with the use of histamine antagonist.

Mast cells and pulmonary fibrosis. Identification of a histamine releasing factor in bronchoalveolar lavage fluid.

As elevated bronchoalveolar lavage (BAL) fluid histamine levels are noted in patients with pulmonary fibrosis (PF), we assayed BAL fluid from 16 patients with PF for the presence of a histamine releasing factor (HRF). HRF activity was assayed by measuring release of the preformed mast cell-derived mediators, histamine, or beta-hexosaminidase (beta-hex) from a purified population of IL-3 dependent mouse bone marrow derived mast cells (MBMMC) or human blood basophils. Mean BAL cell free histamine levels in the patients with PF was 1226 +/- 1349 pg/ml, whereas BAL histamine levels in a comparison group of six non-PF patients was 118 +/- 60 pg/ml. HRF was significantly elevated in BAL fluid of patients with PF (mean beta-hex release 24.5 +/- 12.9%; range 6.8 to 52.4%) compared to the non-PF group of patients (mean beta-hex release 7.9 +/- 7.7%; range 1.8 to 20.7%). The PF HRF not only degranulated MBMMC, but also induced the generation of the arachidonic acid metabolite leukotriene C4 from MBMMC (24.6 +/- 4.2 ng leukotriene C4/10(6) MBMMC). The PF HRF did not appear to be a cytokine previously identified in BAL fluid of patients with PF (i.e., platelet derived growth factor or insulin growth factor-1) or a human cytokine able to degranulate human basophils (i.e., IL-1, or granulocyte-macrophage-CSF) as these recombinant human cytokines did not induce MBMMC beta-hex release. Physicochemical characterization of the HRF revealed that it was relatively heat stable, pronase sensitive and on Sephadex G-75 and G-200 column chromatography had an apparent molecular mass of 30 to 50 kDa. The ability of PF BAL to induce beta-hex release from MBMMC was not dependent on IgE as unsensitized or lactic acid treated MBMMC release similar amounts of beta-hex compared to MBMMC sensitized with IgE. Thus, BAL fluid of patients with PF contains an HRF that induces beta-hex release from MBMMC via an IgE-independent mechanism. The presence of the HRF could explain elevated BAL histamine levels in patients with PF.

Plasma Elevations of Histamine and a Prostaglandin Metabolite in Acute Bronchiolitis

Acute bronchiolitis (AB) is a common lung disease in infants manifested clinically by dyspnea and wheezing. The purpose of this study was to measure simultaneous plasma levels of histamine and a stable prostaglandin F2 alpha metabolite [13,14-dihydro-15-keto-PGF2 alpha (PG metabolite)], by radioenzymatic and radioimmunoassays, respectively, during and after recovery from AB. Blood was obtained from 15 infants during AB and from 14 and 9 of these infants when re-evaluated 6 and 18 months later, respectively. Mean (+/- 1 SEM) pre- and posttherapy (inhaled isoetharine) histamine levels (pg/ml), 1,923 +/- 980 and 1,035 +/- 250 during AB, respectively, were markedly higher than those of the same nonwheezing subjects at 18 months, 360 +/- 125, but unexpectedly lower than those at 6 months, 9,210 +/- 5,242. Of the 14 infants evaluated at 6 months, 7 had elevated histamine levels along with histories of recurrent wheezing after AB. Similarly, pre- and posttherapy PG metabolite levels (pg/ml), 1,033 +/- 419 and 1,613 +/- 527, respectively, were significantly higher than those of the same children when asymptomatic at 6 (27 +/- 7) and 18 months (68 +/- 25). Pre- and posttherapy levels of histamine and PG metabolite were higher than those of normal and sick, nonwheezing infants. These data indicate that histamine and PG metabolite are detectable in plasma during AB and suggest a role for histamine and PGF2 alpha in the pathogenesis of airways inflammation in AB.

Evidence for Elevated Levels of Histamine, Prostaglandin D2, and Other Bronchoconstricting Prostaglandins in the Airways of Subjects with Mild Asthma

Histamine and certain cyclooxygenase products of arachidonic acid have been implicated as mediators of inflammation and are potent constrictors of human airways. Because asthma may represent manifestations of chronic inflammation of the airways, the levels of histamine and six prostanoid mediators were measured in airway fluids obtained by bronchoalveolar lavage (BAL) of 12 normal, 11 allergic rhinitic, and 15 asymptomatic, allergic asthmatic subjects. Simultaneous profiling of prostanoid mediators in individual samples was performed using gas chromatography-mass spectrometry. Levels of PGD2, 9 alpha,11 beta-PGF2 and PGF2 alpha were 12 to 22 times higher in asthmatic than in normal subjects (p less than 0.01), with concentrations in airway fluids of asthmatic subjects after correction for dilution of 3.8, 0.5, and 1.4 nanomolar, respectively. Levels of PGD2 and 9 alpha,11 beta-PGF2 were increased nearly tenfold in asthmatic subjects compared with those in rhinitic subjects (p less than 0.01), distinguishing the subjects with lower airway disease from those with another atopic condition. Histamine levels were increased fourfold in asthmatic subjects compared with those in normal subjects (p less than 0.001); however, similar increases were found in rhinitic subjects. We conclude that elevated levels of multiple mediators with potent bronchoconstricting activity are present in the airways of subjects with mild asthma, indicating that even mild disease is associated with evidence of airway inflammation. The interactions of bronchoconstricting mediators and airway inflammation may play important roles in the pathogenesis of asthma.

Histamine release and pseudoallergic reactions induced by radiographic contrast media: Comparison of Angiographin®, Hexabrix® and Telebrix® using anin vivo canine model

Radiographic contrast media (RCM) in clinical use cause unwanted allergic/pseudoallergic reactions of all grades of severity. They also induce histamine release from a variety of mast cell populations, the extent of the histamine release reaction depending on both the organ and species. In this study 3 RCM, which had been previously shown to be effective histamine releasing agents with canine liver cells, were investigated using an in vivo canine model based on the clinical situation. The dogs (n = 36) were randomly allocated to one of 3 treatment groups and received a bolus injection (2 ml/kg body weight) of either Angiographin, Hexabrix or Telebrix. Blood pressure was monitored continuously and blood sampling, for plasma histamine measurements, was performed before and 1, 5, 10, 20 and 30 min after RCM injection. All 3 RCM caused elevated plasma histamine levels in some animals: Angiographin 9 of 12 dogs, 0.40 ng/ml, (0-1.9 ng/ml) median (range); Hexabrix 11/12, 0.5 ng/ml (0-3.8 ng/ml); Telebrix 7/12, 0.4 ng/ml (0-2.0 ng/ml). Cardiovascular reactions were observed in most animals. The hypotensive reactions occurred with a maximum 30 sec after RCM application and recovery was normally observed after 1-1.5 min. The response after Angiographin or Telebrix was significantly greater than after Hexabrix. Hypertensive reactions occurred later (15 min (5-25 min)) and did not differ between the groups. All 3 agents tested were able to elicit histamine release and cardiovascular reactions. In comparison to histamine release occurring after intravenous administration of other agents, such as hypnotics, the degree of histamine release was small.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of histamine H3-antagonists on human leukocytes

To determine the role of the histamine H3-receptor on basophils, different specific H3-antagonists were investigated. Incubation of washed leukocytes with N alpha-acylated histamine-derivatives (N alpha-ahd) induced elevated histamine levels. This process turned out to be dependent on dose, time and temperature, but independent of Ca2+ and Mg2+ ions. IgE-mediated histamine release was not modulated. [3H]-L-histidine was not decarboxylated into [3H]-histamine in spite of the observed histamine increase. Highly purified basophils did not show any histamine elevation but purified neutrophils and eosinophils were found to have increased histamine levels even after disintegration and subsequent incubation with N alpha-ahd. It seems that the increased histamine levels result from the cleavage of the applied histamine amides. Other potent H3-antagonists (e.g. thioperamide) neither produced increased histamine levels nor influenced IgE-mediated release from basophil leukocytes. The existence of H3-receptors on human basophils therefore seems unlikely.

Elevated Plasma Histamine Levels in Systemic Sclerosis (Scleroderma)

Systemic sclerosis is characterized by excessive deposition of collagen and other matrix proteins in the skin and internal organs. One hypothesis supports fibroblast stimulation for production of excess amounts of collagen by factors present in the blood or released by cells composing inflammatory tissue infiltrates. Increased numbers of mast cells are present in the involved skin of patients with systemic sclerosis, and histamine has been thought to be a possible mediator of fibrosis in this and other fibrotic conditions. We therefore measured plasma histamine levels in 32 patients with systemic sclerosis and found elevated levels in 18 patients (56%). Elevated plasma histamine levels were more common in patients with diffuse disease (74%), in contrast to limited disease (31%). The degree of clinical activity and the duration of disease could not be correlated with histamine levels.