To study the potential role of leukotriene (LTD4) as a mucus secretagogue, anesthetized and spontaneously breathing guinea pigs were intubated and challenged with various concentrations of an LTD4 aerosol. The resulting changes in airway resistance and compliance were then observed for 20 min, after which the animals were euthanized and the lower respiratory tract airways fixed for morphometric evaluation. Sections for these airways were stained with alcian blue-periodic acid Schiff (AB-PAS), photographed, and the content of AB-PAS positive granules in the epithelium of the extrapulmonary bronchi quantified. The fractional volume of mucus granules in the respiratory epithelial volume. Aerosol LTD4 produced a dose-dependent decrease in the granule fractional volume (GFV) over the range of 0.1 to 1 microgram/ml when compared with epithelia challenged with saline aerosols. Increasing the concentration of administered LTD4 from 1 microgram to 3 micrograms/ml produced further bronchoconstriction but had no further effect on the GFV. Decreases in GFV did not appear to be secondary to smooth muscle contraction since aerosols of other agonists (0.05% histamine and 1% acetylcholine), which yielded resistance changes similar to those of LTD4, did not effect the GFV. Pretreatment with an aerosol of the specific LTD4 receptor antagonist SK&F 104353-Z2 produced a dose-dependent inhibition of the changes in both the airway resistance and GFV. The data suggest that LTD4 mediates epithelial mucus secretion as well as bronchoconstriction in the guinea pig airway and may provide an additional therapeutic use for specific LTD4 receptor antagonists in the treatment of obstructive pulmonary disease.