Per E. Alm

Cyclic nucleotide involvement in histamine release from mast cells--a reevaluation.

Secretory events in cells in general are accompanied by increased levels of cyclic AMP. In mast cells, however, the pattern is reversed. Thus histamine release is associated with a fall in cAMP. It has been suggested that the lowered levels of cAMP lead to an increase in membrane permeability towards calcium and that an influx of such ions triggers the release mechanisms. It has further been reported that high levels of cAMP inhibit histamine release by decreasing the permeability. However, evidence has now accumulated indicating that this general concept is far too simplistic. Studies are reviewed which imply that there is little or no correlation between histamine release and intracellular levels of cyclic nucleotides. A new working hypothesis with respect to the role of these nucleotides in mast cell secretion is proposed.

What — if any — is the role of adrenergic mechanisms in histamine release from mast cells?

The effects of catecholamines on histamine release from rat peritoneal mast cells, was studied in an in vitro system. It was found that norepinephrine (10−5–10−3M) exerts a significant, dose related, repressive effect on compound 48/80-induced histamine release. This effect is greatly potentiated by β-antagonists and is noticeable throughout the concentration range 10−11–10−3M norepinephrine. Phentolamine diminishes the repressive effect that norepinephrine shows at 10−5M.Norepinephrine (10−5M) totally inhibits the progressive histamine release induced by both compound 48/80 and strontium (10 μM) in non-Ca2+-depleted cells. The release that is dependent on extracellular calcium is inhibited by norepinephrine.The repressive effect of norepinephrine at 10−3 is counteracted by 5.6 mMd-glucose, 2-deoxyglucose abolishes this effect. The repression of histamine release by 10−5M norepinephrine is not influenced byd-glucose.These results suggest that the effects on histamine release, observed within a low concentration range of norepinephrine (<10−3M), may be due to α-adrenoreceptor mechanisms and an interference in transmembrane calcium transport. Our data further suggest that norepinephrine at 10−3M may inhibit oxidative phosphorylation.Isoproterenol and epinephrine (10−9–10−5M) show little effect on 48/80-induced histamine release in a normal medium. However, when calcium is excluded from the medium, histamine release is potentiated. These results seem to indicate that isoproterenol and epinephrine act by displacing intracellular calcium, making it available for the exocytosis process.

Sodium fluoride evoked histamine release from mast cells. A study of cyclic AMP levels and effects of catecholamines

Calcium triggers the secretion of histamine from mast cells after previous exposure to sodium fluoride. The secretory process can be divided into a fluoride-activation step and a calcium-induced secretory step. It was observed that the fluoride-activation step is accompanied by an elevation of cAMP levels within the cells. The attained high levels of cAMP persist during histamine release. It was further found that catecholamines do not markedly alter the fluoride-induced histamine release. It was also confirmed that the second, but not the first, step in sodium fluoride-induced histamine secretion is inhibited by theophylline.

Effect of norepinephrine on in vitro histamine release from rat mast cells.

The effect of norepinephrine on compound 48/80-induced histamine release from rat peritoneal mast cells, was studied in an in vitro system. It was found that norepinephrine, within the concentration range 10(-5)--10(-3) M, exerts a significant, dose-related, repressive effect. This effect is greatly potentiated by the beta-antagonist practolol (10(-3) M), throughout the concentration range of 10(-11)--10(-3) M norepinephrine. Methoxyamine, a selective alpha-adrenergic agonist, also represses histamine release in a dose-dependent manner; however, it is not as potent as norepinephrine. The present results would seem to suggest that the repressive effect on histamine release, observed within a low concentration range of norepinephrine, may be due to alpha-adrenoceptor mechanisms.

Modulation of mast cell cAMP levels. A regulatory function of calmodulin.

Modulations of cyclic AMP (cAMP) levels and secretory capacity in both immunological and non-immunological stimulation of rat mast cells are influenced by the calmodulin inhibitor trifluoperazine. A model of a calcium-dependent joint regulation of cyclic nucleotide turnover in these two types of mast cell stimulation is presented.

Cyclic AMP levels during stimulation and inhibition of histamine release from rat mast cells by the calmodulin inhibitor trifluoperazine.

The calmodulin inhibitor trifluoperazine represses compound 48/80-induced histamine release. The effects appear to take place at a step distal to the entrance of calcium into the cell. Trifluoperazine in itself induces histamine release from rat peritoneal mast cells. This release is totally independent of extracellular calcium and at high concentrations of the drug (greater than or equal to 20 microM), it is due to lysis of the cells. Trifluoperazine reduces the compound 48/80-induced decrease in mast cell cyclic AMP content, probably by inhibiting a cyclic nucleotide phosphodiesterase. The trifluoperazine-induced repression of histamine release does not seem to be correlated to the ability of the drug to alter the compound 48/80 induced changes in cyclic AMP.

Effects of Norepinephrine on Transmembrane Calcium Transport in Rat Mast Cells

The effect of norepinephrine on transmembrane passage of calcium in rat peritoneal mast cells, was studied in an in vitro system. It was found the histamine release from mast cells induced by the ionophore A 23 187 in normal calcium medium and compound 48/80 in a calcium-free medium was suppressed by 10(-3) M norepinephrine but not at concentrations in the range 10(-5)-10(-4) M. When the secretory process is totally dependent on the presence of calcium in the incubation medium, i.e. calcium-depleted cells, 10(-5) M norepinephrine suppresses the histamine release induced by low concentrations of compound 48/80. The effect of norepinephrine (10(-5) M) on strontium-induced spontaneous" histamine release was also studied. It was found that norepinephrine (10(-5) M) totally inhibits the progressive histamine release induced by strontium. It is possible to evoke secretion in a calcium-free medium, and subsequent introduction of Ca2+ will result in optimal histamine release. This demonstrates a secretory process in which we can distinguish between utilization of endogenous versus exogenous calcium. The release that is dependent on extracellular calcium is inhibited by norepinephrine (10(-5) M). These data indicate that the suppressive effect of norepinephrine (concentrations less than 10(-3) M) on histamine release from rat mast cells is due to an interference in transmembrane passage of calcium.

Surface histamine receptors in rat peritoneal mast cells. Separation of receptor-bearing cells via binding to a histamineprotein conjugate, Cell-ectTM

The Seragen Cell-ect Total Histamine kitTM was used to separate histamine receptor-bearing rat peritoneal mast cells from cells lacking these receptors. It was found that approximately 75% of the peritoneal mast cell population carried cell surface histamine receptors.The results further suggest that the mast cell histamine receptors present are mainly of an H1-type, as judged by the capacity of a specific H1-antagonist to reduce the histamine receptor-dependent cell adhesion. Moreover, an H1-agonist is less efficient in this respect and an H2-antagonist does not affect the cell adhesion at all. A possible functional role for these receptors, however, remains to be clarified.

Anomalous Effects of Disodium Cromoglycate

The effects of disodium cromoglycate (DSCG) on in vitro histamine release from peritoneal and pleural mast cells, and a possible interference with adrenergic mechanisms was studied. Parallel to this s