Original article
Dose-dependent mediation of leukotriene D4-induced airway microvascular leakage and bronchoconstriction in the guinea pig

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Abstract

The i.v. administration of leukotriene (LT)D4 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 ED50 of approximately 0.05 μg/kg. When LTD4 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 H1 histamine receptor antagonist, pyrilamine. When LTD4 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 LTD4. In addition, i.v.-administered LTD4 (0.3 or 1.0 μg/kg) or the prostaglandin (PG)/TXA2 receptor agaonist, U-46619 (3.0 μg/kg), produced significant bronchoconstriction as measured by increases in pulmonary insufflation pressure. The bronchoconstrictor responses to LTD4 were markedly attenuated by the same inhibitors, namely meclofenamic acid, SQ 29,548, and pranlukast, that reduced the 0.3 μg/kg LTD4-induced plasma extravasation throughout the airways and the 1.0 μg/kg LTD4-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. LTD4 are mediated through a direct and an indirect pathway which includes the formation of cyclooxygenase product(s) which act at PG/TXA2 receptors. The pattern of inhibition of the LTD4-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. LTD4 suggests that the phospholipase(s) activated to produce the substrate for cyclooxygenase metabolism are pranlukast sensitive.

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