Calcium antagonists and histamine secretion from rat peritoneal mast cells

The calcium antagonists verapamil and nifedipine inhibited histamine release induced from rat peritoneal mast cells by a number of secretory stimuli. However, the concentrations required were much higher than those active in smooth muscle preparations. The inhibition was unaffected by elevated levels of external calcium and the drugs prevented release in the absence of added calcium. The novel calcium antagonist, PY 108-068, had no effect on histamine secretion from mast cells. These results suggest that calcium channels in the mastocyte may differ from those in smooth muscle and that at concentrations required to inhibit secretion, verapamil and nifedipine may have non-specific stabilizing effects on the mast cell membrane.     

Nicotine and pyrrolidine-induced release of 5-hydroxytryptamine and histamine from neoplastic mast cells

Nicotine and other pyrrolidines induce the release of the components of the multivesicular granules of mouse neoplastic mast cells, including 5-HT (serotonin), histamine and heparin. The elevation of the pH required for the compounds to show activity makes a mast cell site available for the chemical initiation and the maintenance of the release process. At the optimum pH, only the pyrrolidine ring of the nicotine molecule is needed for activity.     

Canatoxin triggers histamine secretion from rat peritoneal mast cells.

Canatoxin, a toxic protein present in the seeds of Canavalia ensiformis, induces the secretion of serotonin, dopamine and insulin through activation of the lipoxygenase pathway. The purpose of the present study was to verify if canatoxin causes histamine release from rat peritoneal mast cells and to perform a detailed study of this phenomenon. Our results indicate that canatoxin is capable of activating mast cells to release histamine. The process is time- and concentration-dependent, occurs without cell damage and requires metabolic energy as well as the presence of divalent cations (Ca2+ and Mg2+). Optimal release occurs at 37 degrees C and at physiological pH. Extremes of temperature (0 degree C and 45 degrees C) inhibit the process. We conclude that canatoxin induces histamine release from rat peritoneal mast cells by an active secretory process.     

Differential release of histamine and 5-hydroxytryptamine from rat mast cells: the contribution of amine uptake to the apparent pattern of secretion.

Despite the fact that mast cells isolated from rat mesentery and lung tissue contain 5-HT in excess of histamine, the pattern of amine output, in response to compound 48/80, mirrors that in peritoneal mast cells where histamine is in excess of 5-HT, such that this secretagogue induces a greater percentage release of histamine than 5-HT. Mast cells are capable of taking up both these amines, although uptake of 5-HT is in preference to that of histamine. With concentrations of clomipramine and fluoxetine that inhibited 5-HT uptake, the net percentage release of 5-HT increased in a corresponding manner, and the concentration-effect curves in response to compound 48/80 ran in a collinear fashion with that of control histamine output (measured in the absence of the drugs). Both drugs had no effect upon the uptake or secretion of histamine. Thus, observed differences in the apparent pattern of histamine and 5-HT secretion from rat mast cells may be due to selective reuptake of amines rather than a reflection of differential amine release.     

Effect of lanthanide ions on histamine secretion from rat peritoneal mast cells.

1 Ions of the lanthanide series (lanthanum-lutetium) inhibit histamine release induced by allergen and anti-IgE in the presence of extracellular calcium. The inhibition is dose-dependent in the range 10(-6) to 10(-9) M and there is no marked difference in potency between the lanthanides. 2 The response to lanthanum is biphasic and higher concentrations (10(-4) M) potentiate the release. Maximal concentrations (10(-3) M) again abolish secretion. 3 The effect of concanavalin A is weakly antagonized by lanthanum but strongly inhibited by higher lanthanides. 4 Inhibition of histamine release evoked by basic agents is markedly dependent on the ionic radius of the lanthanide. In the presence of extracellular calcium, dysprosium is the most effective inhibitor. Similar results are observed with dextran. In the absence of calcium, there is a regular increase in inhibition with decreasing ionic radius. 5 Inhibition of release in the presence of calcium is immediate and does not require preincubation with the lanthanide. The antagonism due to lanthanum is competitive and the pA2 values vary with the secretagogue. In contrast, the inhibitory effect in the absence of extracellular calcium increase progressively with time. 6 These results are discussed in terms of the calcium-pools important in histamine release and the mode of action of different secretagogues.     

Kinetics of the inhibitory effect of flavonoids on histamine secretion from mast cells

The effect of cromoglycate and of natural flavonoids on histamine release from peritoneal rat mast cells induced by compound 48/80 and ionophore A23187 was studied according to preincubation time of mast cells with drugs and to incubation time of cells with the triggering agent. Preincubation of cells with cromoglycate, dihydroquercetin and amentoflavone, a biflavonoid, decreased the potency of drugs to inhibit the ionophore-induced release; the optimal inhibitions were observed when drugs were added simultaneously with the ionophore A23187. In contrast, a short preincubation (2 min) of cells with quercetin or luteolin decreased their inhibitory effect on the ionophore-induced release, whereas a longer preincubation increased the inhibition. When compound 48/80 was used to trigger histamine secretion, the inhibitory potencies of all the compounds used were decreased according to preincubation time. Dihydroquercetin (taxifolin), previously considered as inactive, showed an interesting cromoglycate-like behaviour.     

On the mechanism of dextran-induced histamine secretion from rat peritoneal mast cells

The mechanism of histamine release induced from isolated rat peritoneal mast cells by clinical dextran was examined in detail. The putative involvement of cell-fixed IgE antibodies in the process was discounted by a number of experimental approaches. Instead, the characteristics of the release were found to be consistent with the interaction of the polysaccharide with specific glucoreceptors on the mast cell membrane.     

Parallel secretion of endogenous 5-hydroxytryptamine and histamine from mast cells stimulated by vasoactive peptides and compound 48/80.

The peptides, neurotensin, substance P, somatostatin, and bombesin, several analogues and fragments of neurotensin and compound 48/80, all caused the secretion of both endogenous 5-hydroxytryptamine (5-HT) and histamine. There was no differential effect of any of the secretagogues tested on the secretion of 5-HT and histamine. Amitriptyline prevented the secretion of histamine in response to stimulation by neurotensin, substance P, somatostatin or compound 48/80 but was without effect on the secretion of endogenous 5-HT.     

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.     

Dual effect of magnesium on compound 48/80-induced histamine secretion from rat peritoneal mast cells.

The effect of magnesium on the secretory response to compound 48/80 from rat peritoneal mast cells was studied. The decrease in secretion caused by calcium deprivation was enlarged by magnesium. Glucose partially counteracted the decrease caused by calcium deprivation but not the one caused by magnesium. The addition of calcium to the cells simultaneously with compound 48/80 completely restored the secretory response if magnesium was present. The response was only partially restored in a magnesium- and glucose-free medium, whereas it was almost completely restored if glucose was present. Magnesium had a considerable effect on the restoration of the secretory response of EGTA-treated cells, whereas the effect of glucose was minimal indicating that an effect on the energy metabolism was of minor importance. The secretory response could also be restored by an exposure of the cells to calcium prior to stimulation with compound 48/80. This was, however, only observed if magnesium was present and glucose had no effect. The influence of magnesium on the restoration of the secretory response may partly occur by an effect on the energy metabolism, partly by an effect on the stimulus-secretion coupling. We propose that insufficient supply of Mg2+ to the G-protein during activation by compound 48/80 might cause a suboptimal signal transduction.     

The effect of platelet-activating factor on histamine release from rat peritoneal mast cells.

The effect of platelet-activating factor (PAF) on histamine release from peritoneal mast cells of adult and young male rats was investigated. PAF alone tended to release histamine from the mast cells of adult and young rats, although very slightly. On the other hand, PAF significantly inhibited the histamine release induced by the Ca2+ ionophore A23187 in mast cells obtained from rats of either age group, but not that by compound 48/80. Such inhibition was not seen with lyso-PAF. CV-3988, a PAF antagonist, antagonized the inhibitory effect of PAF on the A23187-induced histamine release in mast cells from adult and young rats. These results suggest that PAF does not have a strong histamine-liberating action on mast cells, and that PAF inhibits the calcium influx into mast cells through the activation of PAF receptors.     

Inhibitory effect of phloretin on histamine release from isolated rat mast cells

The ability of the flavonoid phloretin to inhibit histamine release from rat mast cells varied considerably with the releasing agent investigated. The response to the combination of the ionophore A23187 and the phorbol ester TPA and to suboptimal concentrations of the ionophore (0.5 microM) was potently inhibited (IC50 about 5 microM), whereas phloretin was less potent against responses to the ionophore (1 microM) (IC50 of 17 microM), to antigen alone and in combination with TPA (IC50 of 30-50 microM), to TPA in the absence of calcium (IC50 of 50 microM) and to compound 48/80 in the absence and presence of calcium (IC50 of 60-90 microM). The inhibition by phloretin at concentrations above 10 microM was partly counteracted by glucose (5 mM) indicating effects on oxidative metabolism. The flavonoid quercetin was equally potent in inhibiting histamine release induced by antigen, the ionophore at different concentrations and in combination with TPA (IC50 of 20 microM). Although not conclusive, the results are consistent with an inhibition of protein kinase C by phloretin at concentrations below 10 microM. At higher concentrations unspecific actions become apparent and phloretin therefore seems to be of limited utility as a probe for signal-pathways in cell responses.     

Effect of calmodulin inhibitors on histamine secretion from mast cells

Histamine secretion from isolated peritoneal mast cells was inhibited by a number of calmodulin antagonists. The characteristics of the inhibition were consistent with an action after calcium influx. The rank order of potency of the compounds correlated approximately with their reported anti-calmodulin activity. These data provide tentative support for the involvement of calmodulin in stimulus-secretion coupling in the mast cell.     

A comparison of histamine secretion from peritoneal mast cells of the rat and hamster

Functional mast cells have been obtained by peritoneal lavage of the rat and hamster. Both cell types released histamine on stimulation with appropriate dilutions of anti-rat IgE and anti-hamster serum. The maximum response evoked by each reagent was significantly greater for the hamster cells. The release was non-cytotoxic and was in each case blocked by the corresponding soluble antigen. The rat and hamster cells responded to concanavalin A and the lectin from lentil. Phosphatidylserine (PS) potentiated the release only from the rat cells. In the absence of the lipid, the hamster cells were more reactive. The lectin from wheat germ, in the presence of PS, evoked histamine secretion only from the rat cells. Both populations were refractory to the lectin from soybean and to protein A. Rat peritoneal cells were more responsive to the basic secretagogues compound 48/80 and peptide 401 (the MCD-peptide from bee venom). These differences were less marked in the case of polylysine and polyarginine. The two cell populations responded to the calcium ionophores A23187, ionomycin and chlortetracycline. The hamster cells were significantly more sensitive to the former two liberators but markedly less reactive to chlortetracycline. Adenosine 5'-triphosphate (ATP) and dextran were potent histamine liberators from the rat cells but were totally ineffective against the hamster. Acetylcholine and carbamylcholine had no effect on either cell type. These results are discussed in terms of the functional heterogeneity of mast cells from different sources.     

Effect of ketotifen and oxatomide on histamine secretion from mast cells

The anti-histaminic drugs ketotifen and oxatomide have a dual effect on rat peritoneal mast cells. At high concentrations they induce histamine release, whereas at low concentrations they inhibit secretion evoked by IgE-directed ligands. The latter effect is observed in the presence and absence of exogenous calcium. The significance of this result for the general mode of action of anti-anaphylactic drugs is discussed. Neither compound liberates histamine from isolated mesenteric cells from the rat or guinea pig, further emphasizing the functional heterogeneity of mast cells from different sources.     

Anthracycline-induced histamine release from rat mast cells

Comparisons were made of the ability of doxorubicin, daunorubicin, rubidazone and aclacinomycin A to release histamine from rat peritoneal mast cells. Preliminary in vitro experiments indicated that doxorubicin (10(-6) to 2.5 X 10(-4) M), in contrast to compound 48/80 and the calcium ionophore A23187, did not produce significant release under any condition tested when purified or unpurified rat mast cells were used. In in vitro experiments, released histamine was measured in the cell-free supernatant of peritoneal fluid of rats after intraperitoneal injection of the agents. The time course of doxorubicin-induced histamine release from the peritoneum was rapid, with maximal release occurring within 4 to 6 min. Dose-response curves of the 4 agents over the range 10(-5) to 3.3 X 10(-3) M revealed that all caused histamine release, with 10(-3) M concentrations of each causing maximal release of comparable magnitude to that produced by 9.5 X 10(-6) M A23187. Treated mast cells recovered from the peritoneal cavity showed degranulation and vacuolization when examined by electron microscopy. Increased vascular permeability by the Evans-blue test was also noted with all 4 agents, and zones were of comparable size after injection of the highest concentration of each agent. The results indicate that in vivo, doxorubicin, daunorubicin, rubidazone and aclacinomycin A cause a rapid release of histamine from rat mast cells and an increase in vascular permeability in rat sin. There also appeared to be a reasonable correlation between the blueing reaction and histamine release in the peritoneal cavity in that the doses that did not cause skin blueing also failed to cause histamine release. The lack of histamine release by doxorubicin from mast cell preparations in vitro suggests that alterations to the doxorubicin molecule or the presence of other critical substances may be necessary for this activity to commence.     

Inhibitory effect of lysophosphatidylcholine on the histamine release from rat peritoneal mast cells

Histamine release from isolated rat peritoneal mast cells induced by compound 48/80 (0.5 microgram/ml) or antigen-antibody reaction was inhibited by lysophosphatidylcholine in a dose-dependent fashion at concentrations up to 4 microM. Within the same range of concentration, lysophosphatidylcholine exhibited a membrane-stabilizing action on the model membrane systems decreasing the permeability of lipid bilayer and the fluidity of liposomal membrane in the liquid crystalline state. At concentrations higher than 8 microM, lysophosphatidylcholine damaged the cell membrane and subsequently histamine was released. It was assumed that lysophosphatidylcholine may act as an endogenous membrane stabilizer inhibiting histamine release in normal mast cells.     

Some further characteristics of histamine secretion from rat mast cells stimulated with sodium orthovanadate

Sodium orthovanadate induced a release of histamine from rat peritoneal mast cells. Other oxyanions of vanadium with the metal in the +V oxidation state also evoked histamine release but neither vanadyl sulphate (+IV oxidation state) nor the analogous orthophosphate anion were effective secretagogues. The release evoked by vanadate was selectively inhibited by the anion channel blocker SITS, and by theophylline and Bu2cAMP, but was unaffected by disodium cromoglycate and lanthanum ions. These results are discussed in terms of the possible mode of action of vanadate.