The effect of synthetic leukotrienes (LT) C4, D4 and E4 on the permeability of the airway microvasculature to plasma albumin was quantitatively evaluated using an in situ guinea pig tracheal model. Vascular permeability was measured as extravascular albumin content by employing 125I-bovine serum albumin and, in order to correct for blood volume, 51Cr-erythrocytes were used. Intratracheal injection of synthetic LTC4, LTD4 and LTE4 (0.1-1000 ng) produced dose-dependent increases in tracheal extravascular albumin content. The leukotrienes were approximately 100-1000 fold more potent than histamine, although histamine did produce a greater maximal increase in extravascular albumin than the leukotrienes. Methacholine did not increase extravascular albumin content. The microvascular permeability effect of LTD4 was antagonized by FPL 55712 but not by mepyramine; conversely, the effect of histamine was antagonized by mepyramine and not by FPL 55712. Additionally, indomethacin did not alter the LTD4-induced increases in tracheal vascular permeability. These results suggest that the effect of LTD4 on tracheal microvascular permeability is directly mediated and is not the indirect result of cholinergic stimulation, histamine release or de novo synthesis of cyclooxygenase products.