Among the active substances released during anaphylaxis in guinea-pig lung is a hitherto unidentified substance which has a contracting effect on rabbit aorta. The release of this compound is antagonized by anti-inflammatory agents.

Release of Additional Factors in Anaphylaxis and its Antagonism by Anti-inflammatory Drugs

,8-IMINAZOLYLETHYLAMINE is the amine which is produced when carbon dioxide is split off from histidine. It was first prepared synthetically by Windaus and Vogt'. Recently Ackermann2 obtained a large yield of the base by submitting histidine to the action of putrefactive organisms. It has been shown that several of the amines thus related to amino-acids possess marked physiological activity. The activity of j8-iminazolylethylamine was discovered in the course of the investigation of ergot and its extracts by G. Barger and one of us3, who attributed this structure to a base which they obtained, and which in minute doses produced tonic contraction of the uterus. The synthetic substance, and the base produced by splitting off carbon dioxide from histidine by bacterial action or by chemical means, were found to have an identical action. Meanwhile Kutscher4 had simultaneously and independently described the isolation from ergot of a base having this action and presumably identical with that obtained by Barger and Dale. By its chemical properties this first ergot base of Kutscher was not distinguishable from 8-iminazolylethylamine; but certain apparent differences in the physiological action of the two bases, observed by Ackermann and Kutscber-5, led them to the conclusion that the ergot base, though closely related to 8-iminazolylethylamine, is not identical with it. The alleged difference in action, on the existence and cause of which our experiments throw light, was as follows: the

The physiological action of β-iminazolylethylamine

We describe a guinea pig model of asthma in which animals were sensitized and challenged by inhalation of aerosolized ovalbumin. Challenge was performed under cover of mepyramine (10 mg/kg) to allow a high enough concentration of ovalbumin to elicit consistent late responses. Airway resistance and thoracic gas volume of conscious guinea pigs was assessed by whole body plethysmography before and at regular intervals for as long as 72 h after challenge. At the same time points, cellular changes in the lung were assessed by both examination of cells recovered by bronchoalveolar lavage (BAL) and lung histology. There were no significant changes in specific airway conductance (SGaw), BAL cell content or lung histology in animals challenged with saline control. Challenge with 2% ovalbumin caused an early fall in SGaw, which peaked at 2 h and amounted to a 43.7 +/- 4.1% fall from baseline. This was followed by 2 late responses, the first reaching maximum at 17 h with a 46.9 +/- 4.5% decrease in SGaw from baseline and the second at 72 h with a 39.0 +/- 3.5% fall in SGaw. Examination of BAL fluid revealed a 7-fold increase in neutrophils at 6 h and a 17-fold increase at 17 h, after which numbers decreased to baseline. Eosinophilia developed more slowly, being insignificant at 6 h and 6-fold at 17 h; by 72 h, eosinophils constituted 48.9 +/- 6.9% of the total cells recovered. No changes in mononuclear cells or lymphocytes were observed. Histologic examination of the lung revealed a progressive eosinophil infiltration of the airways, but not alveoli or vascular bed. Electron microscopy showed degranulation of eosinophils recovered by BAL and discharge of mucus from goblet cells in the trachea. Because these changes are similar to those that occur after allergen challenge in human asthma, we suggest that this represents a useful animal model in which to study the mechanism of early and late bronchoconstriction responses.

Early and late-phase bronchoconstriction after allergen challenge of nonanesthetized guinea pigs. I: The association of disordered airway physiology to leukocyte infiltration

This work studies the temporal development of the acute anaphylactic bronchoconstriction in guinea-pigs sensitized to ovalbumin by different regimens, including IgE-antibody promoting ones. The results show that guinea-pigs sensitized with low amounts (1-10 micrograms) of ovalbumin together with alum produce the most pronounced bronchospasm when challenged with an intravenous injection of a low dose of antigen. Examination of the antibody classes by PCA technique shows that guinea-pigs sensitized with small amounts of antigen together with alum produced IgE and IgG1 antibodies. However, in sera from animals immunized with large amounts of antigen, only IgG1 antibodies could be detected.

Antigen-induced bronchial anaphylaxis in actively sensitized guinea-pigs. Pattern of response in relation to immunization regimen.

HISTAMINE, slow reacting substance in anaphylaxis (SRS-A) and prostaglandin F2α (PGF2α) are among substances obtained from lungs that contract human isolated bronchial muscle1–4. Fenamates antagonize bronchoconstriction induced by SRS-A but not that induced by histamine, and they lessen anaphylactic bronchoconstriction in the guinea-pig in vivo5–7. In view of the possibility, arising from these observations, that fenamates might be useful clinically against pathological bronchoconstriction, we explored how far meclofenamate (sodium N-(2,6-dichloro-m-tolyl) anthranilate)8 and flufenamate (sodium N-(α,α,α-trifluoro-m-toryl) anthranilate)9 antagonized the contraction of human isolated bronchial muscle induced by histamine, SRS-A or PGF2α.

Antagonism by Fenamates of Prostaglandin F 2α and of Slow Reacting Substance on Human Bronchial Muscle

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G. W. L. James

Papers

Humoral factors affecting pulmonary inflation during acute anaphylaxis in the guinea-pig in vivo.