A. Truneh

Role of intra- and extracellular calcium in histamine release from rat peritoneal mast cells

The present study provides evidence for a number of calcium pools important in histamine secretion from the mast cell. Firstly, calcium loosely bound to the cell membrane, and in rapid equilibrium with the extracellular environment, may be utilized for histamine release induced by most secretagogues. Secondly, all inducers are able to mobilize deeply buried or internal stores of calcium to initiate exocytosis. Finally, calcium bound to regulatory sites in the membrane may modulate the secretory process. Removal of calcium from the latter sites by brief treatment with chelating agents markedly enhances the secretory response in the absence of extracellular calcium, probably by facilitating the mobilization of bound stores of the ion. Saturation of these sites in the presence of excess calcium inhibits the release process and may restrict influx of the cation.

Calcium Pools Involved in Histamine Release from Rat Mast Cells

Basic secretagogues, antigen, concanavalin A, the ionophore A23187 and, to a lesser extent, anti-rat IgE produce a significant release of histamine from rat peritoneal mast cells in the absence of extracellular calcium. This release is due to the mobilization of intracellular reservoirs of calcium. The release is abolished by prolonged exposure to chelating agents, but is potentiated by brief exposure to these substances. It is suggested that the latter treatment removes calcium from a superficial, regulatory site and thus facilitates the mobilization of more internal pools of the ion. By analogy with smooth muscle, these regulatory sites may also modulate calcium influx into the cell. On the basis of these and other results, the possible calcium pools important in histamine secretion are discussed.

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.

Role of cyclic AMP in the induction of histamine secretion from mast cells.

AbtractImmunological activation of rat peritoneal mast cells induced a transient elevation in the intracellular concentration of cyclic AMP. Enhancement or suppression of this rise by appropriate adenosine analogues produced parallel changes in histamine secretion. However, pharmacological activation of the cell with a number of diverse ligands induced histamine release without any accompanying changes in cyclic AMP. Moreover, this release was modulated by adenosine analogues in identical fashion to IgE-directed ligands but again without affecting cyclic AMP. On the basis of these results, the possible role of cyclic AMP in the induction of histamine secretion is critically considered.

Characteristics of and Calcium Requirements for Histamine Release from Rat Peritoneal Mast Cells Treated with Concanavalin A

Concanavalin A (Con A) produced a selective release of histamine from rat peritoneal mast cells in the presence and absence of added calcium. Secretion under both conditions was enhanced by adenosine, but only the former release was potentiated by phosphatidyl serine (PS). The latter release was abolished by depletion of intracellular reservoirs of calcium and probably reflected mobilization of these stores. A brief exposure to chelating agents enhanced the response to Con A whereas supramaximal concentration of calcium depressed the response. This result suggests that superficial calcium-stores in the membrane may regulate movement of the cation into the cytosol. The activated state induced by Con A and PS was particularly stable and did not decay with time over a 30 min period. The kinetics of the release process were independent of added calcium, indicating that calcium-translocation is not the rate-limiting step in the exocytotic mechanism.

Effect of cyclic AMP, disodium cromoglycate and other anti-allergic drugs on histamine secretion from rat mast cells stimulated with the calcium ionophore ionomycin

Cyclic AMP analogues and the anti-allergic drugs disodium cromoglycate, quercetin, doxantrazole and theophylline inhibited histamine secretion from rat peritoneal mast cells stimulated with the calcium ionophore ionomycin. The potency of the compounds varied inversely with the concentration of ionophore and with the period of incubation. The drugs were active in both the presence and absence of extracellular calcium. These results cannot be explained in terms of the postulated effect of the compounds on the receptor-mediated activation of calcium-channels. Alternative mechanisms for their action are thus considered.

Effect of Anti-Allergic Compounds on Histamine Release from Rat Peritoneal Mast Cells Treated with Concanavalin A

The anti-allergic drugs theophylline, doxantrazole, quercetin, dibutyryl cyclic AMP, and disodium cromoglycate prevented histamine release induced by concanavalin A in both the presence and absence of extracellular calcium. The compounds were generally most effective in the absence of added calcium and least effective in the simultaneous presence of calcium and phosphatidyl serine. The activity of the test drugs in calcium-free media clearly cannot be explained in terms of their postulated ability to block movement of the ion from the external environment into the cell. Alternative modes of action are thus considered.

Some Characteristics of Histamine Secretion from Mast Cells Treated with Ionomycin

The ionophorous antibiotic ionomycin released histamine from rat peritoneal mast cells in both the presence and absence of added calcium ions. The response under the latter conditions was potentiated by brief pretreatment of the cells with chelating agents. The interaction between the ionophore and exogenous calcium was complex. Supramaximal concentrations of calcium potentiated the release induced by low levels of ionomycin but markedly inhibited the secretion evoked by larger amounts of the compound. Dispersed mesenteric mast cells of the rat and guinea pig also responded to ionomycin but were less reactive than the peritoneal cells.