In vivo and in vitro inhibition of histamine release by calcium antagonists.
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Biomedical subjects
Publications and source records attributed to S Norn.
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In this study of intrinsic asthma (IA) in children the pathogenic role of bacteria in respiratory disease was elucidated by a basophil histamine liberation technique. Several strains of bacteria caused release of histamine from peripheral leukocytes in vitro. Normal, non-infectious and non-atopic children frequently responded in a similar fashion, although positive responses were less frequent. It seems that two different mechanisms of bacterial histamine release exist: interaction with the basophil-bound IgE and a direct interaction with the cell surface. It is suggested that the histamine release takes place only in the lung of IA patients, where a defective pulmonary barrier could permit the bacteria to enter, but not in healthy individuals.
In vitro formation of immune complexes was studied by 3H-serotonin release from human platelets by P. aeruginosa antigens in the presence of serum from 22 cystic fibrosis patients, chronically infected with mucoid P. aeruginosa (CF + P) and with a pronounced antibody response against these bacteria, and in 24 patients without P. aeruginosa (CF-P). All CF + P patients responded with 3H-serotonin release (16-34%), whereas CF - P patients released less than 15%. In group of CF + P patients the number of P. aeruginosa precipitins was correlated to the serotonin titer. Time courses indicated that 3H-serotonin release was maximal between 2 and 5 min, and that no further release was observed up to 20 min. There was a gradual increase in 3H-serotonin release with higher platelet concentrations. The response was not changed by complement inactivation, and fractionation of serum demonstrated that the serotonin release was dependent on the presence of the immunoglobulin fraction. These experiments support the suggestion of a type III reaction being involved in the lung damage in CF + P patients and also suggest a possible involvement of serotonin in he inflammatory reaction during chronic P. aeruginosa lung infection.
An in vitro pilot study was performed to determine whether basophil cell-bound specific IgE was correlated to serum-specific IgE and to basophil cell sensitivity during immunotherapy with a well-documented treatment. The findings showed a clear dissociation between these three parameters, which is in contrast to the situation before hyposensitization and to our previous study in a comparable group of non-hyposensitized patients, where highly significant correlations were observed. Further investigations are in progress to clarify whether the dissociation is involved in the clinical improvement.
Twelve children, aged 4 to 14 years, with moderate to severe intrinsic asthma (IA) were studied. Symptom-Score charts were used to confirm the relationship of acute respiratory tract infections to exacerbations of asthma. Hypersensitivity to eight commonly occurring bacteria from the normal flora of the upper respiratory tract was studied by skin test, by crossed immunoelectrophoresis, and by basophil histamine release in vitro, using ultrasonicates of the bacteria as antigens. Skin tests were all negative. All children contained low titers of precipitating antibodies against most of the bacteria, but in this respect they did not differ from normal children. In contrast, release of histamine was induced in leukocytes from the IA children by all, or most sonicates, while such reactions, were less frequent in control children. The pattern of responses indicated an element of specificity. These was no correlation to precipitating antibodies, or to the microbial flora of the children. Positive responses were characterized by low values of maximal histamine release, and by a tendency to fluctuations with time. Because of these fluctuations, and because the IA children and control children were tested on separate occasions, we cannot be certain as to the real difference between these two groups. Our studies do, however, demonstrate that water-soluble constituents of all the bacterial strains tested were capable of causing the release of histamine in vitro, but that this phenomenon is not restricted to IA. The clinical significance of these findings awaits further investigations on the mechanism(s) of release in vitro by such agents.
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Preseasonal hyposensitization stimulated an intercorrelated increase in both serum-specific IgE and allergen-specific IgG. Subsequent perennial treatment depressed the stimulated IgE response and the basophil cell sensitivity, whereas the allergen-specific IgG response showed further increase and persisted at a high level. Nasal IgE response was stimulated from the second pollen season and subsequently became depressed. One year after the end of hyposensitization the allergen-specific IgG response had fallen by 25-50%.
The influence of histamine on human platelet function was studied by thrombin-induced serotonin release. The thrombin-induced 3H-serotonin release was confirmed to be a rapid process which does not require external calcium. Histamine was found to reduce the release of serotonin and the inhibition was abolished when H1-plus H2-antagonists were added together with histamine. H1- and H2-receptor stimulation was examined in two ways, by a combination of histamine with cimetidine or diphenhydramine and by the selective agonists 2-(2-pyridyl)-ethylamine and impromidine. In both instances H1- and H2-stimulation was found to reduce the platelet serotonin release. These results suggest a regulatory role of histamine in the platelet function by stimulation of platelet H1- and H2-receptors.
A comparative study was made on tobramycin combined with either carbenicillin (500 mg/kg/day) or one of the new penicillins: azlocillin or piperacillin (both 300 mg/kg/day) in 50 cystic fibrosis patients with chronic Pseudomonas aeruginosa infection. Average 2-h levels of penicillins in serum were 46 micrograms/ml (piperacillin), 88 micrograms/ml (azlocillin) and 66 micrograms/ml (carbenicillin). The Pseudomonas strains were significantly more sensitive to piperacillin and azlocillin than to carbenicillin (minimal inhibitory concentrations 1.9, 2.3 and 4.2 micrograms/ml). In 21 of 54 treatment course temporary eradication of Pseudomonas was achieved. Improved ventilatory capacity and diminished proteolytic activity in sputum were seen in most patients with or without bacteriological treatment success. Resistant strains - often belonging to other types - appeared in the patients with treatment failure. With increased number of precipitating antibodies against Pseudomonas and with increased minimal inhibitory concentrations, the chance of eradication was smaller. Seven out of 20 treated with azlocillin and 14 out of 30 treated with piperacillin developed fever and exanthema by the end of treatment. Our experience suggests caution in the use of the new penicillins.
Basophilocytes from patients with rheumatoid arthritis (RA) responded to leukocyte nuclei from normal persons with histamine release; a similar histamine release induced by the nuclear components RNA and DNA has been demonstrated previously. A role of histamine in RA is also supported by the findings of clinical improvement during treatment with H1 and H2 antihistamines in six of 12 patients with RA in active phase, whereas four showed definite deterioration.
A double-antibody radioimmunoassay for measurement of grass pollen antigen-specific IgG in serum is described. Grass pollen antigens were used to show a correlation between the results obtained by this method and those obtained by measuring blocking antibodies by inhibition of antigen-induced leukocyte histamine release. The new technique described is convenient, sensitive, specific and reproducible and can be recommended for clinical use.
The involvement of an allergic reaction directed against nuclear components and aggregated IgG was examined by basophil histamine release technique in chronic bronchitis (CB) in the intrinsic type of bronchial asthma (IA). In the group of 21 CB patients, seven responded to RNA, DNA or histone and three responded to aggregated IgG. In the other group of seven IA patients one responded to RNA and histone. In comparison with healthy blood donors the prevalence of smooth muscle antibodies was increased in CB patients and antinuclear antibodies were increased in both groups of patients. The findings suggest an involvement of an allergic reaction directed against RNA, DNA, histone, and aggregated IgG in some patients with CB and IA. This may play some role in the reversible airway obstruction of these diseases.
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Basophil histamine release by P. aeruginosa standard antigen was examined in cystic fibrosis patients chronically infected with mucoid P. aeruginosa (CF +P) and with pronounced antibody response against these bacteria, and in patients without P. aeruginosa infection (CF +P). All the patients showed eosinophil counts and total IgE, which did not differ significantly from that of normal persons. In the absence of patient's sera, histamine release was only found in two patients in the CF +P group, indicating that type I allergy to P. aeruginosa is not predominating in cystic fibrosis. In the presence of patients' sere significantly more of the CF+P patients responded to P. aeruginosa with histamine release compared with the CF-P patients. The response was lost by complement inactivation and regained by reconstitution of the complement activity. The involvement of a type III-mediated complement-dependent histamine release is therefore suggested in the pathogenesis of lung damage in cystic fibrosis.
Sixteen of 84 cystic fibrosis patients developed skin manifestations during intensive carbenicillin therapy. The possibility of allergic drug reactions was examined. None of the patients showed any significant levels of antibodies of IgE, IgG or IgM classes against carbenicillin and different penicilloyl determinants as recorded with RAST, sandwich-radioimmunoassay and double antibody assay. The leukocytes of the patients did not release histamine on in vitro provocation with carbenicillin. Furthermore, none of the patients responded to prick test or to peroral penicillin provocation. The negative findings indicated that the recorded reactions were most probably not due to antibody-mediated allergy of type I or type III.
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Experiments in the skin and synovialis have thrown new light on the allergic-inflammatory reactions. The inflammatory effect of histamine is thus due to stimulation of two different types of receptors in the vessels, i.e. histaminergic H1 and H2 receptors. Both types of receptors are of importance for the immediate cutaneous response to allergens and histamine. Treatment with a combination of H1 antagonists (classical antihistamines) and the H2 antagonist cimetidine will thus cause a much stronger inhibition of the urticarial reactions than treatment with the H1 and H2 antagonist alone. It is therefore probable that a combination therapy could have an advantage over the traditional treatment with classical antihistamines in urticaria and other histamine-mediated skin diseases. Histamine might also be of importance for the swelling of the joints in inflammatory diseases such as rheumatoid arthritis, and clinical trials with H1 and H2 antagonists are in progress.