L-663,536 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2, 2-dimethylpropanoic acid) is a potent inhibitor of leukotriene (LT) biosynthesis in intact human polymorphonuclear leukocytes (PMN) (IC50, 2.5 nM). Similarly, L-663,536 inhibited A23187-induced LTB4 formation by rat peripheral blood and elicited PMN. At concentrations where inhibition of leukotriene biosynthesis occurred in human whole blood (1.1 microM), no effect was seen on cyclooxygenase or 12-lipoxygenase, an effect also observed in washed human platelets. The compound had no effect on rat or porcine 5-lipoxygenase indicating that L-663,536 is not a direct 5-lipoxygenase inhibitor. When administered in vivo L-663,536 was a potent inhibitor of antigen-induced dyspnea in inbred rats pretreated with methysergide (ED50, 0.036 mg/kg p.o.) and of Ascaris-induced bronchoconstriction in squirrel monkeys (1 mg/kg p.o.). The compound inhibited leukotriene biosynthesis in vivo in a rat pleurisy model (ED50, 0.2 mg/kg p.o.), an inflamed rat paw model (ED50, 0.8 mg/kg), a model of leukotriene excretion in rat bile following antigen provocation, and a model in the guinea-pig ear where leukotriene synthesis was induced by topical challenge with ionophore A23187 (ED50, 2.5 mg/kg p.o. and 0.6 micrograms topically). The results indicate that L-663,536 is a potent inhibitor of leukotriene biosynthesis both in vitro and in vivo indicating that the compound is suitable for studying the role of leukotrienes in a variety of pathological situations.

Male Dunkin Hartley guinea pigs, actively sensitized to ovalbumin (OA) and pretreated with mepyramine (1 mg/kg i.p.), were challenged with OA as an aerosol. Histological analysis of the lung for eosinophils (EOs) showed significant accumulations in the submucosa of the airways (8 h: 1,477.3 ± 43 EOs/mm² airway, n = 3, p < 0.01), after antigen challenge compared to saline control (478.6 ± 104 EOs/mm² airway, n = 4). Pretreatment with both mepyramine and cimetidine (10 mg/kg i.p.) did not affect this response. Aerosolization of OA to unsensitized guinea pigs resulted in no significant accumulation of EOs (360.2 ± 49 EOs/mm² airway, n = 4) when compared with the saline-challenged sensitized control group. Pretreatment with the leukotriene (LT)D₄ receptor antagonist MK-571 (1 mg/kg p.o.) significantly inhibited the OA-induced EO migration (95 ± 5% inhibition, n = 5, p < 0.01) compared to vehicle in the presence of mepyramine and cimetidine, while indomethacin (3 mg/kg p.o., n = 4) had no effect. Aerosolization of synthetic LTC₄ (0.3–30 μg/ml) resulted in a dose-dependent migration of EOs into the submucosal layer over 8 h, reaching significance at the 10-μg/ml dose, with comparable results obtained with LTD₄. Pretreatment of animals with MK-571 (1 mg/kg p.o.) before LTC₄ and LTD₄ aerosol results in inhibition of the response in both cases, suggesting that this effect may be mediated through the LTD₄ receptor. We conclude that peptide LTs produce eosinophilia in the airways of the guinea pig.

Airway and pulmonary vascular smooth muscle was obtained from the surgically resected lobe of a human asthmatic allergic to grass pollen who presented with an endobronchial carcinoid tumor. Grass antigen induced sustained contractions of bronchial and pulmonary vein, but not pulmonary artery tissue. Capsaicin did not alter the bronchial response to grass antigen. Contractions to leukotrienes B₄, C₄, D₄ and E₄ and methacholine were equivalent to those seen in nonasthmatic human lung tissue, whereas those to histamine were strikingly greater and disproportionate to methacholine. The C3a octapeptide Ala-Ala-Ala-Leu-Gly-Leu-Ala-Arg produced contractions of pulmonary vein and pulmonary artery. These findings are compared with those obtained using human lung samples from nonasthmatic individuals.

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