Robert P. Orange

Inhibition of the release of slow-reacting substance of anaphylaxis in the rat with diethylcarbamazine.

Summary The immunologic release of SRS-Arat with intravenously administered antigen is described. Hetrazan effectively inhibits the antigen-induced release of SRS-Arat in a dose of 20 mg/kg iv. In this concentration, it has no influence on the bioassay system and does not prevent effective antibody-antigen interaction. Hetrazan does not produce an irreversible inhibition and must be present at the time of antibody-antigen interaction to effectively prevent the formation and release of SRS-Arat. Suppression of the 4-hour PCA reaction in the rat with Hetrazan plus mepyramine maleate and methysergide suggests that SRS-Arat may be a permeability factor involved in this reaction.

Cyclic adenosine 3',5'-monophosphate in human lung.

Abstract Cyclic[ 14 C]adenosine 3′,5′-monophosphate (cyclic AMP) in human lung fragments has been measured by an isotopic method. It was found that aminophylline transiently increased cyclic[ 14 C]AMP by 100% in doses above 1 mM. β-Adrenergic agents, epinephrine and isoproterenol, increased cyclic [ 14 C]AMP by greater than 1000% through at least 10 min of incubation. Combinations of isoproterenol and aminophylline acted synergistically. Norepinephrine alone increased cyclic[ 14 C]AMP but to a lesser degree than isoproterenol or epinephrine. In the presence of β-adrenergic blockade, norepinephrine and epinephrine decreased cyclic [ 14 C]AMP below control values.

Pharmacologic Dissociation of Immunologic Release of Histamine and Slow Reacting Substance of Anaphylaxis in Rats

Summary A study of the structural analogs of diethylcarbamazine reveals the requirement for a carboxamide grouping and a saturated or unsaturated ring containing nitrogen for optimal inhibition of SRS-Arat release. Diethylcarbamazine and its analogs do not act by interfering with PMN leukocyte viability and they do not inhibit the homocytotropic antibody-mediated release of histamme and serotonin. Conversely, disodium cromoglycate suppresses the latter pathway without inhibiting the antigen-induced release of SRS-Arat. Neither diethylcarbamazine nor disodium cromoglycate antagonizes the pharmacologic activity of histamine or SRS-Arat. The use of these agents permits further dissociation of the pathways leading to the immunologic release of SRS-Arat and histamine in the rat by selective pharmacologic inhibition.

The effects of H1 and H2 receptor antagonism on the response of monkey skin to intradermal histamine, reverse-type anaphylaxis, and passive cutaneous anaphylaxis.

The effects of H1 and H2 receptor anatagonists on models of allergic reactions in monkey skin have been studied. Intradermal histamine is markedly inhibited by H1 receptor antagonists but not by H2 receptor antagonists in the doses used. However, the combination of both receptor antagonists gives greater inhibition than that seen with H1 receptor blockade alone. Reverse-type anaphylaxis is also markedly inhibited by H1 but not H2 receptor antagonists. Passive cutaneous anaphylaxis (PCA) is likewise inhibited by H1 receptor antagonism, but not by H2 receptor antagonism. The combination of the two inhibitors leads to a complete inhibition of this PCA response. The data suggest that the addition of an H2 receptor antagonist may potentiate the effect of H1 blockade alone.

Release of slow-reacting substance of anaphylaxis in the rat: Polymorphonuclear leukocyte

The antigen-induced release of slow-reacting substance of anaphylaxis was studied in rats previously treated with different biological and pharmacological agents to deplete these animals of specific cellular elements. The polymorphonuclear leukocyte appears necessary as a crucial cell type for optimum release of the slow-reacting substance of anaphylaxis, whereas the mast cell and lymphocyte are not required.

Prostaglandin Inhibition of the Immunologic Release of Slow Reacting Substance of Anaphylaxis in the Rat

Summary The prostaglandins, PGE1 and PGE2, effectively inhibit the IgE- and IgGa-mediated release of SRS-A in the rat in a dose-response fashion. Structure-function studies suggest that the carbonyl group in the 9 position, the position of a double bond in the cyclopentane ring, and either the degree of saturation of the cyclopentane ring or the presence of the hydroxl group in the 11 position, or both, are required for optimal inhibitory activity. Indirect evidence did not establish that prostaglandin inhibition of SRS-A release is mediated through an increase in tissue cyclic AMP levels and no synergism between PGE1 and diethylcarbamazine or diso-dium cromoglycate was demonstrable.

Prospects in Asthma Therapy: Disodium Cromoglycate and Diethylcarbamazine

Asthma is a syndrome of varying etiology in which the principal pathologic features include bronchospasm, mucosal edema and hypersecretion of mucus resulting in ventilatory insufficiency manifested...

Chemical Mediators of Immediate Hypersensitivity

Two chemical substances, histamine and s R S-A, mediate the immunologic interactions that may eventuate in immediate hypersensitivity or anaphylactic reactions. Defining the pathways, initiated at the adrenergic receptor sites, through which these mediators are elaborated has made it possible to evaluate the antianaphylactic usefulness of such blocking agents as diethylcarbamazine and sodium cromoglycate.

Further evidence on the structure of slow reacting substance of anaphylaxis (SRS-A).

Arachidonic acid stimulates the release of SRS-A from the peritoneal cavity of sensitized rats or from rat peritoneal cells incubated in vitro. When rat peritoneal cells are incubated in the presence of tritiated arachidonic acid, significant amounts of radioactivity migrate in parallel to bioactivity on purification with Amberlite XAD-8, DE-52, Silicic acid and Sephadex LH-20.Lipoxidase (E.C. 1.13.1.13 and E.C. 1.13.11.12) inactivates mouse, rat and human SRS-A in a concentration-dependent pattern. Following extensive purification, rat SRS-A is also inactivated by the 2×crystalline suspension of lipoxidase. These findings suggest (a) that SRS-A is a metabolite of arachidonic acid and (b) because of the strict specificity of lipoxidase, that the SRS-A molecule contains acis, cis-1, 4-pentadiene and a structure very close either to arachidonic acid, to linoleic acid or to linolenic acid.

The Immunological Release of Chemical Mediators of Immediate Type Hypersensitivity from Human Lung**Supported by grants AI-07722 and FR-05669 from the National Institutes of Health and a grant from the John A. Hartford Foundation.

Publisher Summary This chapter discusses the immunological release of chemical mediators of immediate-type hypersensitivity from human lung. The investigation of the in vitro release of chemical mediators from human lung following antigen–antibody interaction represents a study of an inflammatory process initiated by an immunologic trigger, which can be defined, isolated, and quantitated. This experimental model permits identification not only of the participating immunoglobulins but also of the biochemical events involved in the immunologic release of the chemical mediators. The apparent diversity of the mediators released from lung tissue subsequent to antigen–antibody interaction underlines the need for the definition of common control mechanisms susceptible to specific inhibition. The chapter describes the slow-reacting substance of anaphylaxis and the eosinophil chemotactic factor of anaphylaxis.