calcimycin and 2--5--dideoxyadenosine

In keeping with previous reports, immunological activation of purified rat peritoneal mast cells induced a transient elevation in the intracellular concentration of cyclic AMP which preceded or accompanied the release of histamine. Enhancement or suppression of this rise by appropriate adenosine analogues produced parallel changes in histamine secretion. However, the purinoceptor antagonist theophylline prevented the augmented rise in cyclic AMP induced by adenosine analogues but did not affect the enhancement of histamine release. In addition, pharmacological activation of the cell with a number of diverse ligands induced histamine release without any accompanying changes in cyclic AMP. This release was modulated by adenosine analogues in identical fashion to IgE-directed ligands but again without affecting cyclic AMP levels. These data clearly show that adenosine can augment histamine release independently of adenylate cyclase and seriously question the significance of the early rise in cyclic AMP as a causal event in immunological secretion of the amine.

Topics: Adenosine; Animals; Calcimycin; Concanavalin A; Cyclic AMP; Deoxyadenosines; Dideoxyadenosine; Dipyridamole; Histamine Release; Immunoglobulin E; In Vitro Techniques; Ligands; Mast Cells; p-Methoxy-N-methylphenethylamine; Peritoneal Cavity; Phenylisopropyladenosine; Rats; Rats, Inbred Strains; Theophylline

2',5'-Dideoxyadenoside (DDA) inhibited both anti-IgE and ionophore A23187 induced histamine secretion from human basophils. Whereas DDA inhibited IgE-dependent histamine secretion when added at all times prior to challenge, release induced by A23187 was inhibited only with simultaneous addition of DDA and secretagogue. Dipyridamole, but not theophylline, abrogated DDA mediated inhibition of histamine release suggesting an intracellular mechanism of action of DDA. The observations that 2'-deoxyadenosine and 9-beta-D-arabinofuranosyladenine also inhibited release suggest that the its inhibitory effect was enhanced by manganese and reversed by islet activating protein from Bordetella pertussis suggest that DDA inhibits basophil histamine release by interacting with a guanine nucleotide binding protein which may be linked to either adenylate cyclase or other second messenger system(s).

Topics: Adenosine; Basophils; Calcimycin; Cell Separation; Deoxyadenosines; Dideoxyadenosine; Histamine Release; Humans; Immune Sera; Immunoglobulin E; Kinetics; Vidarabine

The purine nucleosides adenosine and 2',5'-dideoxyadenosine (2',5'ddAdo) enhance and inhibit respectively the anti-IgE-induced secretion of histamine and transient rise in cellular levels of cyclic AMP in rat mast cells. These findings have provided evidence for a role for cyclic AMP in the activation of mast cell secretion. It has been generally accepted that the nucleosides mediate their effects on mast cells by altering adenylate cyclase activity. We have investigated the effect of various purine and ribose modified analogues of adenosine on secretion of histamine from rat mast cells induced by ionophore A23187 for which there is no associated elevation in cyclic AMP and no evidence for the activation of adenylate cyclase in its mechanism of action. Adenosine and N6, phenylisopropyladenosine (0.01-1000 microM) (activators of adenylate cyclase in many tissues) enhanced the secretion of histamine induced by ionophore A23187 and anti-IgE. Two inhibitors of adenylate cyclase had differential effects on secretion. 2',5'ddAdo (100-1000 microM) inhibited both A23187-and anti-IgE-mediated secretion; whilst 9-beta-D-arabinofuranosyladenine had no effect on secretion. These results suggest that the ability of these nucleosides to modulate histamine secretion is unrelated to their effects on adenylate cyclase.

Topics: Adenosine; Animals; Calcimycin; Deoxyadenosines; Dideoxyadenosine; Histamine Release; Immunoglobulin E; Male; Mast Cells; Phenylisopropyladenosine; Rats; Rats, Inbred Strains; Structure-Activity Relationship; Vidarabine