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Membrane perturbing activity of beta-adrenoceptor blocking drugs in isolated rat mast cells.

Beta-adrenoceptor blocking (BAB) drugs perturb the membranes of isolated rat mast cells. Membrane fluidisation was temperature dependent and was determined by the liposolubility of the BAB drugs. The secretory index, evaluated as the ratio between histamine liberation and degranulation, correlated with the membrane order parameter of the mast cell membranes. The rank order of potency for mast cell activation and membrane fluidisation was: exaprolol greater than propranolol greater than metipranolol greater than atenolol.

Adrenergic beta-Antagonists↗

Studies on histamine secretion from enzymically dispersed cutaneous mast cells of the rat.

A method has been developed for the enzymic dissociation of rat skin into its component cells. The resulting suspensions contained 3-5% mast cells. The latter were intact as judged by light microscopy and exhibited a low spontaneous release of histamine. Cells obtained from actively sensitized animals released histamine on challenge with specific antigen. The process was rapid, being essentially complete within 1 min, and was both calcium-and temperature-dependent. The cells also responded to antirat IgE and to calcium ionophores but showed a selective, time-dependent reactivity toward defined chemical histamine liberators. On the basis of these results the properties of the cutaneous mast cell are compared with those previously reported for mastocytes from other sources and discussed in terms of the general heterogeneity of this cell population.

Animals↗

Release of mediators from human gastric mucosa and blood in adverse reactions to benzoate.

A study was carried out on 29 patients to investigate the amount of histamine liberation and release of platelet-activating factor and 6-keto-prostaglandin F1 alpha from gastric mucosa and whole blood or mononuclear cells by sodium benzoate. The patients suffered from asthma (10), atopic dermatitis (7) and chronic urticaria (4). 8 patients with unrelated, non-immunologic diseases served as controls. In the oral provocation test (OPT) 3 patients experienced a recurrence of their original disease, whilst 1 asthmatic patient reacted with abdominal disorder. The release of histamine and prostaglandin from mucosa was significantly increased by sodium benzoate in comparison to the spontaneous release observed in patients. The mucosa of the control persons did not react to sodium benzoate. Furthermore, there was a significant difference in prostaglandin release between patients with positive OPT and the control persons. No difference could be found between patients with negative OPT and those with positive OPT. Additionally, in the mediator release from whole blood or mononuclear cells there was no obvious difference apparent. These results suggest a possible involvement of prostacyclin and histamine in adverse reactions to benzoate. Due to the sensitivity of the method, a mediator release from mucosa can already be demonstrated in a preclinical state of the pseudoallergic reaction in the absence of clinical symptoms.

6-Ketoprostaglandin F1 alpha↗

Influence of grenz rays and psychological factors on experimental pruritus induced by histamine and compound 48/80.

The interaction between grenz rays and experimentally induced pruritus was evaluated in 14 healthy subjects. Grenz rays were administered once weekly for 4 weeks on restricted areas of the upper arms. Pruritus was evoked by intradermal injection of histamine and the histamine liberator compound 48/80. The results were compared with unconditioned values and with those obtained following a placebo treatment procedure. The influence of psychosocial and psychosomatic factors was also evaluated. Grenz-ray therapy reduced itch but not flare responses. The influence of grenz rays was, however, not statistically different from that observed after placebo treatment. Psychosocial and psychosomatic factors were good predictors of individual skin responsiveness. The results indicate that grenz rays do not interfere with experimental histamine-induced pruritus more than placebo and emphasize the importance of knowing individual characteristics and coping strategies.

Adult↗

Permeability increase in black lipid membrane induced by compound 48/80.

When compound 48/80, a potent histamine liberator, was added in the aqueous phase facing the black lipid membrane, the conductivity of the membrane was remarkably increased. Although valinomycin displayed a distinct selectivity for K+ movement, such selection for ionic permeability was not observed in the case of compound 48/80.

Animals↗

Effect of hyposensitization for tree pollinosis on associated apple allergy.

Twenty patients suffering from birch pollen allergy received two or three courses of immunotherapy in successive years. In 9 patients, the fruit allergy improved; 4 patients reported no improvement. In 3 patients, the fruit allergy developed after beginning the immunotherapy. At the end of the 3 years, 16 of these patients were allergic to fruit, 13 of them to apple. After each preseasonal course of immunotherapy with tree pollen extract, a temporal and parallel increase in the titers of IgE antibodies to birch pollen allergens and apple allergens were observed. In contrast, only the titers of birch pollen allergen specific IgG and IgG4 increased, whereas apple allergen specific IgG and IgG4 did not, or only very slightly. In Western blot studies, IgG4 antibodies bound to more components of apple extract than birch pollen extract. On the average, IgG4 antibodies recognize more components of apple and birch pollen extracts than do IgE antibodies. In histamine release studies, the sensitivity of washed leukocytes to birch pollen extract decreased significantly during the observation time. However, the difference between apple extract-induced histamine release before and after immunotherapy was not significant. None of the immunological parameters investigated here correlate well with severity or prognosis of the fruit (apple) allergy. The clinical improvement of pollinosis was associated with a rise in birch pollen specific IgG4 antibody titers and a decrease of allergen-induced histamine liberation. Beside improvement of the fruit allergy in 56% of the cases, the courses of apple specific IgE and IgG4 antibody titers seem to indicate a slight sensitization against apple allergens.

Adult↗

Basophil histamine release by RNA, DNA and aggregated IgG examined in rheumatoid arthritis and systemic lupus erythematosus. Results compared with basophil counts and antinuclear antibodies.

Basophils from patients with rheumatoid arthritis (RA) respond to RNA, DNA and immune complexes (aggregated IgG) with histamine release. The RNA response was well correlated to the clinical activity of the disease, since histamine liberation was found in all patients with severe activity, whereas no liberation was observed in patients with moderate or quiescent activity. A less significant correlation was obtained with DNA and aggregated IgG. In contrast, no response was obtained with RNA, DNA and aggregated IgG in patients with systemic lupus erythematosus (SLE) or in controls. In the RA and the SLE groups no significant correlation was found between the response of RNA, DNA and aggregated IgG and the serum titres of anti-DNA and antinuclear antibodies. No difference in basophil cell count in peripheral blood and basophil histamine content was found between RA, SLE and controls. Our results point to an involvement of an autoimmune type I reaction in the pathogenesis of RA directed against the nuclear components RNA and DNA and against immune complexes.

Adolescent↗

Morphological and histochemical studies on a PAS-positive granular leukocyte in blood and connective tissues of Catostomus commersonii Lacépède (teleostei:pisces).

This study was undertaken to identify an ubiquitous granular leukocyte found in Catostomus commersonni Lacépède. The cell contains large, numerous, strongly PAS-positive cytoplasmic granules, an eccentric nucleus and prominent, persistent juxtanuclear space. It develops in the hemopoietic tissue of the kidney, and mature cells are found not only in kidney and peripheral blood but also in areas of connective tissue where mast cells are usually located. Electron microscopy confirms the presence of a large Golgi apparatus, unlamellated cytoplasmic granules and extensive rough-surfaced endoplasmic reticulum. Histochemical studies show that the cytoplasmic granules are alcianophobic, non-metachromatic and unstained by acridine orange. Histamine is detectable spectrophotometrically in kidney tissue, but the PAS-positive granular leukocyte does not consistently degranulate after treatment with histamine liberator 48/80. The authors suggest that while the PAS-positive granular leukocyte is not identical with classical basophils/mast cells, which are absent in C. commersonnii, it may represent an evolutionary precursor of these cells.

Animals↗

A comparative study of histamine secretion from rat peritoneal and pleural mast cells.

The effects of various histamine liberators and inhibitors on isolated rat peritoneal and pleural mast cells have been compared. The pleural cells showed an increased reactivity to challenge with antigen following passive, but not active, sensitization and were more responsive to challenge with anti-IgE. Phosphatidyl serine enhanced the secretion from both cell types. Peritoneal and pleural cells exhibited virtually identical responses after treatment with chemical secretagogues in the presence of exogenous calcium, but the peritoneal cells were significantly more reactive to stimulation with basic inducers in the absence of the cation. Anaphylactic histamine secretion was comparably inhibited by a number of anti-allergic drugs but the peritoneal cells were rather more sensitive to inhibition by dibutyryl cyclic AMP. These results are discussed in terms of the general functional heterogeneity of mast cells from different sources.

Anaphylaxis↗

Degranulation of mast cells located in median eminence in response to compound 48/80 evokes adrenocortical secretion via histamine and CRF in dogs.

The effect of intracerebroventricular infusion of compound 48/80 (C48/80), a mast cell secretagogue, on adrenal cortisol secretion was investigated in dogs under pentobarbital sodium anesthesia. A marked increase in adrenal cortisol secretion was elicited by C48/80 along with a concomitant increase in the plasma levels of cortisol and immunoreactive ACTH, but neither arterial blood pressure and heart rate nor the plasma histamine level altered significantly. Pretreatment with either anti-CRF antiserum or pyrilamine maleate (H(1) histamine-receptor antagonist) significantly attenuated the C48/80-evoked increase in cortisol secretion, but pretreatment with metiamide (H(2)-receptor antagonist) significantly potentiated it. Significant attenuation of the C48/80-evoked increase in cortisol also occurred in dogs given ketotifen, a mast cell stabilizing drug, before pharmacologic challenge. In the pars tuberalis and median eminence (ME), mast cells were highly concentrated in close association with the primary plexus of the hypophysial portal system. Degranulated mast cells were extensively found in the ME of C48/80-treated animals. These results suggest that mast cells located in these regions liberated histamine within the brain as a result of degranulation induced by C48/80 and that this led to activation of the hypothalamic-pituitary-adrenocortical axis.

Adrenal Cortex↗

Effect of a low protein diet on the capacity of mice to express a type I hypersensitivity response.

The capacity of Balb/c mice maintained since weaning on a 4% protein diet to express in vivo immediate (type 1) hypersensitivity reactions was compared to that of age-matched animals maintained on a normal (18%) protein diet. The deprived mice had a lower total cellular population and lower mast cell numbers in their peritoneal cavity. However, the mean cellular histamine content was comparable between the two groups. The skin responses of malnourished mice to the histamine liberator 48/80 were depressed but both groups reacted equally to passive cutaneous anaphylaxis when sensitized with serum from immunized mice. These studies indicate that protein deprivation has not inhibited the capacity to synthesize physiologically active amines or to impair the biochemical pathway of amine release from mast cells.

Animals↗

Basophil releasability in human hydatidosis.

We studied immunoglobulin E (IgE)- and non-IgE-mediated releasability in basophils from 31 patients with hydatidosis. Histamine release to non-IgE-dependent stimuli did not differ significantly between normal individuals and patients with hydatidosis. On the contrary, an increased histamine liberation was obtained by challenging basophils from hydatid patients with anti-human IgE. It is concluded that Echinococcus granulosus infection induces an enhanced sensitivity of basophils to IgE-dependent stimuli.

Animals↗

Effects of reserpine and propranolol on urinary excretion of histamine and 5-hydroxytryptamine in severe cold exposure in normal and cold-acclimated Guinea-pigs.

The effects of cold-acclimation, reserpine and propranolol were investigated on the survival time, rectal temperature and urinary excretion of histamine and 5-HT in guinea-pigs at -20 degrees C. Both reserpine and propranolol shortened survival time by 3 hours and 1.5 hours respectively, the shortest time being in the cold-acclimated reserpine-treated animals. There was a trend in severe cold exposure to increased excretion of histamine both in the non-acclimated and in cold-acclimated animals. Reserpine did not change the excretion but increased the concentration of histamine from 0.08 to 0.25 microgram/ml. Propranolol proved to be a histamine liberator by increasing the excretion in non-acclimated from 0.10 to 1.40 microgram/h and concentration from 0.10 to 4.52 microgram/ml and in cold-acclimated animals the excretion from 0.20 to 2.85 microgram/h and the concentration from 0.08 to 3.23 microgram/ml. Severe cold increased the excretion of 5-HT in the non-acclimated animals from 0.08 to 0.21 microgram/h and cold acclimation increased this to 0.17 microgram/h. Reserpine diminished the excretion from 0.08 to 0.03 microgram/h in the non-acclimated animals, but propranolol had no effect. The results showed that the excretion of histamine and 5-HT into urine are changed in cold and can be modified with drugs. The application of the findings in proving a cold stress deserves further study.

Acclimatization↗

Influence of picumast dihydrochloride on the ex vivo histamine release from leucocytes of allergic asthmatic patients.

In a pilot study 8 patients with allergic obstructive airway disease were treated with the new compound picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarine++ + dihydrochloride) 2 x 2 mg daily orally during a period of 8 days additionally to a usual therapy of bronchodilators and corticoids in a steady state. It was demonstrated that the compound inhibited the allergen induced histamine liberation of patients basophils significantly. Compared with a collective of patients without an additional picumast dihydrochloride treatment the effect of the substance was shown more clearly. From reasons of these experimental data picumast dihydrochloride may be of a considerable value as a prophylactic agent in allergic bronchial asthma when given orally.

Asthma↗

Histamine secretion from mast cells stimulated with sodium orthovanadate.

Sodium orthovanadate was found to be an effective histamine liberator from peritoneal mast cells of the rat and mouse. The release process was slow, non-cytotoxic and strongly dependent on pH and extracellular calcium. The effect was highly tissue and species specific and human basophil leucocytes and tissue mast cells of the rat and guinea pig were only weakly responsive or essentially unreactive.

Animals↗

Histamine H1 receptors in C6 glial cells are coupled to calcium-dependent potassium channels via release of calcium from internal stores.

We investigated the action of histamine on C6-astroglioma cells using patch clamp recording and intracellular calcium measurement. Application of 100 microM histamine hyperpolarized the resting membrane potential and increased free intracellular calcium. Membrane hyperpolarization was accompanied by a decrease in input resistance. The effect of histamine was reversible and responses persisted following repeated applications. In voltage clamp experiments histamine elicited an outward current associated with a conductance increase and a reversal potential near the Nernst potential for potassium. The action of histamine was blocked by mepyramine but not by cimetidine or thioperamide suggesting that a H1 receptor mediated the response. Quinidine and charybdotoxin, but not apamin, blocked the hyperpolarization. Buffering internal calcium with BAPTA diminished the activation of the potassium channel, suggesting a calcium-dependent K(+)-channel, which was also found to be regulated by protein kinase C and phosphatases. The increase in intracellular calcium was not dependent on external calcium or sensitive to pertussis toxin, cholera toxin, forskolin or 8-bromo-cAMP. Both the hyperpolarization and the increase in intracellular calcium were blocked by thapsigargin or the phospholipase C inhibitor U73122. These results indicate that histamine liberates calcium from internal stores by activation of phospholipase C which in turn leads to an increase of intracellular Ca2+ and thereby to the activation of a calcium-dependent potassium channel in C6 glial cells.

Animals↗

[Effect of perioperative antibiotic prophylaxis on hemodynamic stability during surgery: detection of complex interaction in a simulated clinical randomized animal study].

In a clinic modelling randomised trial (CMRT) in three groups of 10 land-race pietren pigs each it could be shown that the influence of prophylactic antibiotic administration on intraoperative hemodynamic stability and histamine release is only evident, if by stepwise addition of complicating factors the overall complexity of the experimental setting is increased. Different antibiotic regimen for prophylaxis significantly affected the incidence of cardiovascular instabilities only after relevant blood loss, restoration of circulation and subsequent submaximal induction of anaphylactoid reactions by the histamine liberator Polymyxin B. In conclusion, preclinical testing of therapeutic agents in complex clinic modelling randomised trials should be mandatory to avoid the possible hazards of misconducted clinical trials.

Amoxicillin-Potassium Clavulanate Combination↗

Agonist-antagonist interactions in the skin: comparison of effects of loratadine and cetirizine on skin vascular responses to prick tests with histamine and substance P.

The skin vascular responses (weal, flare, blood flow measurements) elicited by intradermal administration by pricking of histamine (HS) and substance P (SP) were evaluated 6 h after a single intake of anti-H1 agents displaying different activity profile on skin tests at currently recommended dosages (loratadine 10 mg, cetirizine 10 mg) as compared to placebo (P). The weal and flare response and the increases of blood flow occurring in the usual flare area after HS and SP were almost completely abolished by cetirizine. Inhibition of HS- and SP-induced weal and flare reactions was less marked after loratadine and blood flow in the expanding flare after HS and SP showed significant fluctuations over time. In view of the present results and of data obtained in previous experiments with intradermal injection of agonists, we hypothesize that mode of administration of agonists significantly influences the size of the residual weal after anti-H1 agents. We demonstrate that SP weals induced by pricking are largely inhibited by a potent H1 blockade which supports the view that this phenomenon, as well as the SP-flare, is due to SP-induced histamine liberation. We also, for the first time, report on fluctuations recorded at the edge of the developing flare with laser Doppler flowmetry early after prick testing with a weak H1 blockade. This opens up new avenues in dynamically testing H1-receptor occupancy in vivo and in situ in human skin.

Adult↗