The immunologic release of histamine and slow reacting substance of anaphylaxis (SRS-A) from human lung tissue can be enhanced by stimulation with either alpha adrenergic agents (phenylephrine or norepinephrine in the presence of propranolol) or cholinergic agents (acetylcholine or Carbachol). The finding that atropine prevents cholinergic but not comparable alpha adrenergic enhancement is consistent with the view that cholinergic and alpha adrenergic agonists interact with separate receptor sites on the target cells involved in the immunologic release of chemical mediators. The consistent qualitative relationship between the antigen-induced release of mediators and the level of cyclic adenosine monophosphate (cyclic AMP) as measured by the isolation of 14C-labeled cyclic AMP after incorporation of adenine-14C into the tissues or by the cyclic AMP binding protein assay suggests that changes in the level of this cyclic nucleotide mediate adrenergic modulation of the release of histamine and SRS-A. The addition of 8-bromo-cyclic guanosine monophosphate (cyclic GMP) produces an enhancement of the immunologic release of mediators while dibutyryl cyclic AMP is inhibitory. As cholinergic-induced enhancement was not associated with a measurable change in the levels of cyclic AMP, the possibility is suggested that cyclic GMP may be the intracellular mediator of cholinergic-induced enhancement of the immunologic release of histamine and SRS-A.

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The sensitization of human lung with atopic serum is both time and temperature dependent. Highly purified IgE myeloma protein is capable of blocking sensitization of human lung with atopic serum whereas myeloma proteins of the IgG subgroups are inactive. Drugs capable of increasing cellular levels of CAMP such as ß-adrenergic agents and methylxanthines inhibit the antigen-induced release of both histamine and SRS-A from human lung and these agents demonstrate synergism when used together. The ß-adrenergic blocking agent, propranolol, prevents epinephrine-induced inhibition of the immunologic release of the mediators. Diethylcarbamazine also inhibits the antigen-induced release of histamine and SRS-A from human lung and a synergism between this drug and epinephrine is observed. Predominantly α-adrenergic stimulation achieved by combining propranolol with epinephrine or norepinephrine not only prevented the inhibitory activity of the sympathomimetic amines but also resulted in an enhanced release of histamine and SRS-A. These observations suggest that whereas increases in cellular levels of CAMP are inhibitory, decreases in cellular levels of CAMP enhance the antigen-induced release of the mediators.

The immunologic pathways leading to the release of histamine and slow reacting substance of anaphylaxis (SRS-Arat) in the rat can be dissociated in terms of the responsible homolgous immunoglobulins ( 1,2) and the participating target cells (3,4). Histamine release from rat mast cells is mediated by a heat labile ( S ) , "mast cell sensitizing" (6) or homocytotropic (7) antibody; the immunoglobulin class of the homocytotropic anti,body has not yet been established, but it appears to be distinct from the recognized classes, IgG, IgA, and IgM (8,9). The formation and release of SRS-Arat is mediated by a heat stable antibody of the IgGa class (2) and requires the presence of the polymorphonuclear (PMN) leukocyte (3) but not the peritoneal mast cell.The present report ,reveals that these two distinct pathways can be selectively blocked in vivo by pharmacologic agents which act *Supported by Grant AI-07722-02 from the Na-1 Postdoctoral Trainee recipient of NIH Training tional Institute of Allergy and Infectious Diseases.Grant AM-05076-11 from NIAMD. after antigen-antibody interaction but prior to the formation and release of the mediators. Diethylcarbamazine (3, 10) and certain structural analogs prevent the immunologic elaboration of SRS-Arat but not of histamine and serotonin, whereas disodium cromoglycate (1 1) suppresses the antigen-induced release of the amines but does not inhibit the release of SRS-Arat.Materkls. Diethylcarbamazine citrate ( 1diethylcarbamyl-4-methylpiperazine) (Het razan, Lederle Laboratories, Pearl River, New York) was kindly supplied by Dr. H. G. Lockhard (Lederle Laboratories). Disodium cromoglycate ( 1, 3-bis[ 2-carboxychromon-5yloxy ] -2-hydroxypropane) ( FPL-670, Fison's Pharmaceuticals, Loughborough, Leicestershire, England) was