Role of Cyclic AMP During Histamine Release. Histamine Release is not Directly Related to Increase in Cyclic AMP Levels in Rat Mast Cells Activated by Concanavalin A, Anti-IgE, Antigen, Prostaglandin D2and Isoproterenol

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Abstract
Activation of mast cells by bridging of IgE-receptors or concanavalin A (Con A) results in a rapid initial rise and fall in cyclic AMP (cAMP) levels followed by a second rise in cAMP levels and histamine release (Sullivan, T. et al. (1976) J. Immunol. 117, 713-716; Lewis, R.A. et al. (1979) J. Immunol. 123, 1663-1668; Ishizaka, T. et al. (1981) Proc. Natl. Acad. Sci. U.S.A. 78, 6812-6816). trans-4-Guanidinomethylcyclohexanecarboxylic acid 4-tert-butylpheny ester (GMCHA-OPhBut), a strong trypsin inhibitor and an anti-allergic agent (Muramatu, M. et al. (1982) Hoppe-Seyler''s Z. Physiol. Chem. 363, 203-211; Takei, M. et al. Agents Actions, in press), strongly and dose-dependently inhibited the initial and second rises in cAMP levels, and release of histamine from rat mast cells by Con A, anti-IgE and antigen. Addition of GMCHA-OPhBut after the initial rise in cAMP inhibited the second rise in cAMP and histamine release. These results suggested a possible participation of a trypsin-like proteinase, probably pH 7 tryptase present in rat mast cells, in the activation of adenylate cyclase by the above secretagogues, and the initial rise in cAMP was not directly related to the latter events. The second rise in cAMP is induced by prostaglandin D2 (PGD2), a metabolic product of arachidonic acid. PGD2 elevated the cAMP levels in mast cells whereas no histamine was secreted. GMCHA-OPhBut did not inhibit the increase in cAMP by PGD2. Therefore, the strong inhibitory effect of GMCHA-OPhBut on the second rise in cAMP might depend on the inhibition of an earlier process than the activation of adenylate cyclase by PGD2. The addition of anti-IgE or Con A after the maximal increase in cAMP levels in mast cells induced by PGD2 strongly inhibited histamine release from mast cells. Isoproterenol also increased cAMP and induced histamine release, while histamine secretion preceded the increase in cAMP. GMCHA-OPhBut did not show any effect on cAMP rise and histamine secretion by isoproterenol, indicating that the mechanisms of adenylate cyclase activation and histamine secretion by isoproterenol differs from those by Con A and anti-IgE.

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