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From the Children's Asthma Research Institute and Hospital, Denver, Colorado, and the Department of Medicine, Harvard Medical School at the Robert B. Brigham Hospital, Boston, Massachusetts
Abstract
Evidence was presented that agents capable of increasing intracellular levels of cyclic adenosine 3',5'-monophosphate (AMP) also inhibit the direct, antigen-induced and reversed-type release of histamine and slow reacting substance of anaphylaxis (SRS-A) from monkey lung fragments sensitized in vitro with human atopic serum and E myeloma protein, respectively. Beta-adrenergic agents such as isoproterenol and epinephrine, which interact with 
-receptors in tissues and thus activate adenyl cyclase, inhibited the release of both chemical mediators, and this inhibition was prevented by the -adrenergic blocking agent, propranolol. The methylxanthine, theophylline, which acts as a competitive inhibitor of cyclic AMP phosphodiesterase, also inhibited the release of both histamine and SRS-A. A marked synergism was observed when -adrenergic agents and theophylline were used together. Finally, an alkylated derivative of cyclic AMP, dibutyryl cyclic AMP, also inhibited the release of both mediators in a dose-response fashion. Agents that increase cellular levels of cyclic AMP appeared to inhibit the release of histamine and SRS-A at some point subsequent to antigen-antibody interaction and prior to the release of the mediator and in acting at such a site permitted desensitization of the sensitized tissues by specific antigen. Diethylcarbamazine was also found to inhibit the release of both histamine and SRS-A from sensitized monkey lung tissues. This agent demonstrated a remarkable synergism with the -adrenergic agent isoproterenol, but the inhibitory activity of diethylcarbamazine was not prevented by the -adrenergic blocking agent propranolol.
Footnotes
1 This work was supported by Grant GB-8370 from the National Science Foundation, by Grants AI-07722 and FR-05669 from the National Institutes of Health, and by the John A. Hartford Foundation.
2 Present address: Johns Hopkins University, School of Medicine at the Good Samaritan Hospital, Baltimore, Maryland. Reprint requests should be mailed to this address.
3 Postdoctoral Research Fellow of the Helen Hay Whitney Foundation.
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