Apomorphine-induced inhibition of histamine release in rat peritoneal mast cells.

The apomorphine-induced inhibition of histamine release in rat peritoneal mast cells was studied by means of secretagogues stimulating different pathways of mast cell activation. Apomorphine inhibited the mast cell response to all releasing agents (lysophosphatidylserine plus nerve growth factor, compound 48/80, substance P, ATP, tetradecanoylphorbolacetate, melittin). The IC50 ranged from 4 microM to 24 microM at concentrations of secretagogues releasing 30-50% of mast cell histamine. However, the potency of the drug decreased at higher secretagogue concentrations. Mast cells, pretreated with apomorphine and washed, released little histamine upon stimulation. The secretory response could be partially restored on increasing the concentration of secretagogues. The results suggest that apomorphine affects a regulatory step controlling the terminal sequence of mast cell secretory activity. As indicated by the reduced potency of the drug, the control by the apomorphine-sensitive reaction loses efficiency under conditions of massive histamine release.     

Peptides and histamine release from rat peritoneal mast cells

Various vasoactive peptides were compared for their histamine releasing effects on rat mast cells. Neurotensin, substance P (SP), and kallidin were the most active natural peptides, followed by bradykinin; neurokinin A and B, bombesin, angiotensin and tuftsin were practically inactive. Several kinins and tachykinin-related peptides were tested in an attempt to characterize the receptors mediating histamine liberation. The order of potency of the kinins was the following: kallidin greater than [Tyr(Me)8]bradykinin = bradykinin greater than [desArg10]kallidin greater than desArg9-bradykinin, the same as that found in smooth muscle possessing receptors of the B2 type. Tachykinin-related peptides were potent stimulants and followed the order: [D-Tryp7,9,10]SP-(1-11) greater than [D-Pro2,D-Tryp7,9,10]SP-(1-11) greater than SP-(1-11) greater than SP-(1-9) greater than [D-Pro4,D-Tryp7,9,Leu11]SP-(4-11) greater than SP-(1-7) greater than SP-(4-11) greater than neurokinin A = neurokinin B, indicating that: (a) undecapeptide antagonists of SP behave as superagonists; (b) both N- and C-terminal portions of SP-(1-11) are essential for activity; and (c) receptors for the tachykinins mediating histamine release appear to be of the SP-P type.     

Prostaglandin and histamine release from stimulated rat peritoneal mast cells

The production of five prostanoids (PGD2, PGE2, PGF2 alpha, 6-oxo-PGF1 alpha, and TxB2) was examined after mast cell activation. Prostaglandin D2 (PGD2) was the major prostanoid produced after stimulation of rat peritoneal mast cells with the calcium ionophore A 23187, compound 48/80 or anti-rat IgE. The amount of PGD2 generated was not dependent on the quantity of histamine released. The time course of PGD2 production paralleled the release of histamine following activation with A 23187 or anti-rat IgE but with compound 48/80 release of histamine reached a maximum within 15 sec, whereas production of PGD2 was apparent only after 5 min and was still increasing at 30 min.     

Effect of dantrolene on histamine release from rat peritoneal mast cells.

Dantrolene strongly and dose-dependently inhibited histamine release from rat peritoneal mast cells induced by anti-IgE. Dantrolene inhibited Ca(2+)-mobilization from intracellular Ca(2+)-store as well as histamine release in mast cells activated by anti-IgE, the effect on both these phenomena being closely correlated. These results suggested that the effect of dantrolene on histamine release from rat mast cell might be due to the inhibition of Ca(2+)-release from intracellular Ca(2+)-store.     

Effect of cromoglycate on anaphylactic histamine release from rat peritoneal mast cells

Cromoglycate (1-30 muM) produced a concentration-dependent inhibition of anaphylactic histamine release from actively sensitized rat peritoneal mast cells but at lower concentrations (0.01-0.1 muM) occasionally produced a concentration-dependent enhancement of histamine release.     

Induction of histamine release from rat peritoneal mast cells by histatins.

Human salivary histatins (Hsts), which belong to a salivary polypeptide family, have potent antifungal activity against Candida albicans and Cryptococcus neoformans, and are expected to be useful as therapeutic reagents against Candida species. However, little is known about the effect of Hsts on host immune systems. Thus we conducted a series of in vitro experiments with rat mast cells to determine whether histatin 5 (Hst 5) or histatin 8 (Hst 8) has a histamine-releasing effect on mast cells. Both Hst 5 and Hst 8 induced histamine release from rat peritoneal mast cells in a dose-dependent manner (10(-9) to 10(-5) M). Hst 5 had a stronger releasing effect than Hst 8. The histamine release induced by Hst 5 (10(-6) M) was increased by the presence of 0.5 mM Ca2+, but decreased by 2mM Ca2+. Alternatively, the histamine release induced by Hst 8 (10(-6) M) was inhibited by the presence of Ca2+ (0.5 to 2 mM). These results suggest that Hsts have limited usefulness as therapeutic agents due to induction of histamine release from mast cells.     

A peritoneal fluid activator for histamine release from isolated peritoneal mast cells of the rat

A factor present in rat peritoneal fluid has been found to be necessary for optimal release of histamine from peritoneal mast cells by dextran and antigen, but not by concanavalin A. Washed peritoneal mast cells suspended in a physiological medium containing bovine serum albumin require ten-fold higher concentrations of phosphatidyl serine for optimal release by concanavalin A. The peritoneal fluid activator is probably a protein of molecular weight about 180,000 Daltons.     

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.     

Characterization of protease-activated receptors in rat peritoneal mast cells

Activation of protease-activated receptor (PAR)-1 or PAR-2 elicits inflammation most probably via mast cell degranulation in vivo. The present study aimed at characterizing PARs in rat peritoneal mast cells (PMC). Messenger RNA for PAR-1, but not for PAR-2, was detected in PMC. Thrombin, the PAR-1 agonist SFLLR-NH2 or the PAR-2 agonist SLIGRL-NH2 failed to induce histamine release from PMC. Surprisingly, the PAR-2-inactive control peptide LSIGRL-NH2 triggered histamine release from PMC. Thus, PAR-1, but not PAR-2, are expressed in PMC, whereas neither PAR-1 nor PAR-2 are considered to be involved in degranulation of PMC. LSIGRL-NH2 does not appear to be appropriate as a control peptide for PAR-2 in inflammation studies.     

Dual effect of antihistamines on rat peritoneal mast cells: induction and inhibition of histamine release

A variety of H1- and H2-receptor agonists and antagonists are shown to have a dual effect on isolated rat peritoneal mast cells. At high concentrations the drugs induce histamine release while at low concentrations they inhibit the secretion of the amine evoked by antigen. These effects do not appear to be directly related. The ability of the H1-antagonists to inhibit histamine release does not appear to correlate in simple fashion with their recorded pA2 values as measured on the guinea pig ileum, suggesting that the effect is not mediated through H1-receptors. These results are discussed in terms of the clinical utility of antihistaminic drugs.     

Comparative effects of oxatomide on the release of histamine from rat peritoneal mast cells

Oxatomide inhibits the release of histamine from rat peritoneal mast cells in vitro induced by C 48/80, antigen, anti-IgE and ionophore A 23 187, without effect on non-specific release by n-decylamine. Its effect is concentration- and pH-dependent and decreases with increasing extracellular Ca2+-concentrations. Prolonged incubation does not enhance the inhibition, which is lost after one single wash-out. Aminophylline and isoproterenol are not potentiated by oxatomide. The present study points to an effect of oxatomide on a Ca2+-dependent process at the level of cell membrane common to antigen, C 48/80 and ionophore A 23 187.     

Effect of picumast on histamine release from rat cardiac and peritoneal mast cells.

Compound 48/80-induced histamine release (HR) from the isolated perfused rat heart was markedly and significantly inhibited by picumast (PIC), possibly by acting as a calmodulin antagonist (CMA) or membrane stabilizer. Trifluoperazine (TFP, another CMA in clinical use) had a similar effect. However, an action as CMA being the basis of inhibition of HR could not be confirmed in another 'allergy' model, namely HR from rat peritoneal mast cells (RPMC). PIC, TFP and two other CMA, W7 and N-(4-aminobutyl)-5-chloro-1-naphthalenesulfonamide) failed consistently to inhibit 48/80-induced HR from RPMC, and when used on their own at high concentration these compounds caused HR. PIC and TFP also potentiated the heat-induced haemolysis of rat erythrocytes, i.e. lacked membrane stabilizing effect in this model.     

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.     

Recovery of purification-associated reduction in antigen-induced histamine release from rat peritoneal mast cells.

Immunoglobulin E (IgE)-dependent histamine release from purified rat peritoneal mast cells (PMC) is very low in comparison to that from a non-purified preparation (PEC). The reduced histamine release from PMC is recovered or potentiated by reconstitution with separated non-mast cells (NMC). In the present study, further characterization was undertaken to elucidate the mechanisms involved. Sensitized mast cells were recovered from peritoneal cavities of rats, and purified by density gradient centrifugation with Percoll. Effects of NMC reconstitution, membrane fraction of NMC, NMC incubation supernatant, adhesion molecules and extracellular matrix proteins on IgE-dependent histamine release from PMC were examined. IgE-dependent histamine release was significantly potentiated by NMC reconstitution to PMC. The potentiation was dependent on the concentration of NMC reconstituted and reached a plateau after 30 min incubation. Increasing concentration of PMC did not affect the histamine release. Membrane fraction prepared from NMC also potentiated PMC histamine release in a dose-dependent manner. The potentiation reached a plateau in 5 min. Furthermore, incubation supernatant of NMC potentiated PMC histamine release. Antibodies against intercellular adhesion molecule (ICAM)-1, lymphocyte function-associated antigen (LFA)-1, very late activation antigen (VLA)-1, VLA-4 and VLA-6, and fibronectin did not affect the potentiation of PMC histamine release by NMC reconstitution. Fibronectin, laminin and collagen failed to potentiate PMC histamine release. These results indicate that the membrane component(s) of NMC in the rat peritoneal cavity seems to modulate IgE-dependent histamine release from peritoneal mast cells of rats, and that the active molecule(s) may be released from NMC. Adhesion molecules such as ICAM-1, LFA-1 and VLA are not involved.     

Sphingosine inhibition and promotion of histamine release from isolated rat mast cells.

Sphingosine inhibited the histamine release induced by antigen, compound 48/80 with and without calcium, and the combination of TPA and the ionophore A23187. The inhibition occurred in the concentration range 1-3 microM, where no sign of cytotoxicity was noted. Preincubation for 5-10 min was needed for inhibition, and the effect persisted after washing of the cells. No inhibition was found with optimal concentrations of the ionophore or with TPA present during the preincubation. Sphingosine in combination with suboptimal concentrations of the ionophore could induce a considerable histamine release. This response was dependent on energy and was potently inhibited by the flavonoid phloretin. After preincubation with TPA, sphingosine exerted a pronounced potentiation of the response to very low concentrations of the ionophore. The findings regarding inhibitory effects of sphingosine do not seem to be compatible with a selective action on protein kinase C. The ability to synergize with the ionophore and to potentiate the effect of preincubation with TPA resembles previous findings with palmitoylcarnitine and suggests that sphingosine can stimulate mast cells by activation of protein kinase C.     

The measurement of histamine release from suspensions of rat peritoneal cells rich in mast cells.

Histamine released from the mast cells in unfractionated rat peritoneal cell suspensions could be quickly and conveniently measured by an automated chemical method. There were no substances in the unfractionated peritoneal cells that interfered with the chemical histamine measurement. Organic extraction of histamine and deproteinization of samples were not necessary using the automated method. The amount of histamine released from preparations of peritoneal cells by a fixed concentration of compound 48/80 decreased with the time of preincubation of the cells but this varied between preparations. Phagocytic activity directed against the mast cells probably explained these observations. The state of nutrition of the rats and the presence or absence and/or glucose in the medium all influenced the rate of decline of viability of the mast cells.     

Substance P-induced histamine release from rat peritoneal mast cells and its inhibition by antiallergic agents and calmodulin inhibitors.

Substance P-induced histamine release and Ca2+ release from the intracellular Ca store of rat peritoneal mast cells were inhibited by both antiallergic drugs and microtubule inhibiting agents. It was found that in the case of antiallergic compounds, histamine release inhibition may be intimately related to the inhibition of Ca2+ release from the intracellular store in which the microtubules play an important role. When mast cells were pretreated with either theophylline or dibutyryl cAMP, the inhibition of histamine release was closely related to the inhibition of Ca2+ release from the intracellular Ca store. Calmodulin inhibitors were also effective in inhibiting histamine release from mast cells induced by substance P. The inhibitory potencies of calmodulin inhibitors on histamine release from mast cells were closely correlated with those exerted on calmodulin activity.