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Experiments on the metabolism and excretion of i.v. administered selectively labeled [3H8]1eukotriene C4 in bile duct-cannulated guinea pigs indicated predominantly biliary excretion of tritium. The major leukotriene metabolite in bile was identified as leukotriene D4. By monitoring leukotriene excretion radioimmunochromatographically, it was shown that guinea pigs suffering from anaphylactic shock produce leukotriene D4 endogenously. Immunological challenge of animals sensitized to ovalbumin was accompahied by an increase of biliary leukotriene D4 concentrations from 10 ± 1 to 86 ± 10 nM (mean ± SEM, n = 5, P < 0.001). When considering that bile flow was decreased to abobt half after challenge, the excretion rate of leukotriene D4 in bile increased from 0.88 ± 0.16 before to 3.18 ± 0.38 pmolmin-'-kg-' after challenge (mean ± SEM, n = 5, P < 0.002). It is concluded that systemic anaphylaxis in the guinea pig is associated with endogenous generation of leukotriene C4 (Up to 1 nmol/kg during a 30-min period after the challenge).Leukotriene C4 (LTC4) is a biologically active substance presumed to play major roles as a mediator of allergic and anaphylactic reactions (1, 2). It is formed by basophilic (3) and eosinophilic leukocytes (4), monocytes (5), macrophages (6), and mast cells (7). In cells having IgE receptors, bridging of these receptors by divalent anti-IgE receptor antibodies or by interaction between receptor-bound IgE and anti-IgE will induce LTC4 formation (5-7). Leukotriene formation has also been demonstrated in other in vitro models of immediate hypersensitivity (8-10). The biological actions of LTC4 comprise induction of airway obstruction, constriction of coronary arteries, hypotension, and plasma extravasation (11)(12)(13)(14). Leukotriene formation in vivo may mediate anaphylactic shock symptoms and cause the death of an animal. To prove the presumed mediator role of this substance in anaphylactic reactions, it is necessary to demonstrate its endogenous formation during anaphylaxis. Studies on LTC4 metabolism have revealed rapid catabolism by various transformations of the peptide substituent (15). Three metabolites have been demonstrated to be excreted as end-products: leukotriene E4 (LTE4) (16) in man and N-acetyl-LTE4 plus N-acetyl-11-trans-LTE4 (17) in the rat. By monitoring biliary N-acetyl-LTE4 levels, endogenous leukotriene formation in the rat was demonstrated in vivo after tissue trauma and endotoxin shock (18,19). We now wish to report evidence for endogenous LTC4 production during anaphylactic shock in guinea pigs.

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