Dose-dependent mediation of leukotriene D 4-induced airway microvascular leakage and bronchoconstriction in the guinea pig

Abstract

The i.v. administration of leukotriene (LT)D 4 to anesthetized guinea pigs produced dose-dependent increases in pulmonary microvascular permeability, as measured by extravasation of Evans blue dye into the trachea, main bronchi, and small airways, with an ED 50 of approximately 0.05 μg/kg. When LTD 4 was administered at 0.3 μg/kg, the resulting plasma extravasation into all three airway sections was markedly reduced by pretreatment with a cyclooxygenase inhibitor, meclofenamic acid (2.5 mg/kg, i.v.), a thromboxane (TX) receptor antagonist, SQ 29,548 (0.1 or 1 mg/kg, i.v.), or a peptidoleukotriene receptor antagonist, pranlukast (SB 205312) (0.1 or 1 mg/kg, i.v.), but not by the H 1 histamine receptor antagonist, pyrilamine. When LTD 4 was administered at 1.0 μg/kg, meclofenamate (2.5 or 5 mg/kg, i.v.) or SQ 29,548 slightly attenuated plasma extravasation only in the small airway, whereas pranlukast was effective in all three airway segments. Administration of the 5-lipoxygenase inhibitor, zileuton (10 mg/kg, i.v.), or the PAF antagonist, L-659,989 (5 mg/kg, i.v.), did not affect the microvascular leakage response to 1.0 μg/kg LTD 4. In addition, i.v.-administered LTD 4 (0.3 or 1.0 μg/kg) or the prostaglandin (PG)/TXA 2 receptor agaonist, U-46619 (3.0 μg/kg), produced significant bronchoconstriction as measured by increases in pulmonary insufflation pressure. The bronchoconstrictor responses to LTD 4 were markedly attenuated by the same inhibitors, namely meclofenamic acid, SQ 29,548, and pranlukast, that reduced the 0.3 μg/kg LTD 4-induced plasma extravasation throughout the airways and the 1.0 μg/kg LTD 4-induced extravasation into the small airways. U-46619-induced bronchoconstriction was blocked only by SQ 29,548. Based on the profile of antagonists employed in the present studies, we conclude that microvascular leakage and bronchoconstriction elicited by i.v. LTD 4 are mediated through a direct and an indirect pathway which includes the formation of cyclooxygenase product(s) which act at PG/TXA 2 receptors. The pattern of inhibition of the LTD 4-induced bronchoconstriction most closely mimicked the inhibitor profile of microvascular leakage in the small airways, suggesting a greater relative contribution of this site to activity resulting from cyclooxygenase product formation or action. The ability of pranlukast to abolish both responses to i.v. LTD 4 suggests that the phospholipase(s) activated to produce the substrate for cyclooxygenase metabolism are pranlukast sensitive.