LEUKOTRIENE D-INDUCED AND PROSTAGLANDIN F2-ALPHA-INDUCED AIR-FLOW OBSTRUCTION AND AIRWAY PLASMA EXUDATION IN GUINEA-PIG - ROLE OF THROMBOXANE AND ITS RECEPTOR

1 We studied the effects of a thromboxane A2 receptor (TP receptor) antagonist, ICI-192,605 (0.5 mg kg-1, i.v.) and a selective thromboxane (Tx) synthetase inhibitor, OKY-046 (30 mg kg-1, i.v.), on airway responses induced by leukotriene D4 (LTD4; 0.2 nmol) or prostaglandin F2alpha (PGF2alpha; 20 nmol) instilled via the airways route to anaesthetized guinea-pigs. For a comparison, airway responses to a TxA2-mimetic, U-46619 (0.02 nmol) were also studied. We measured both lung resistance (R(L)) to monitor airflow obstruction, and extravasation of Evans Blue dye to quantify airway plasma exudation. 2 Instilled LTD4 into the tracheal lumen induced an immediate peak and subsequently persistent increase in R(L) and produced a large amount of extravasation of Evans Blue dye at all airway levels. Both ICI-192,605 and OKY-046 significantly attenuated the persistent increase in R(L) following the immediate response and reduced LTD4-induced extravasation of Evans Blue dye in the trachea and proximal intrapulmonary airway. Instilled LTD4 produced significant increases in immunoreactive TxB2 in bronchoalveolar lavage fluid obtained 1.5 min after instillation of LTD4. 3 Instilled PGF2alpha into the tracheal lumen induced an immediate increase in R(L) which peaked at approximately 15 s. We also observed a delayed sustained increase in R(L), reaching a second peak at approximately 4 min. PGF2alpha produced small but significant increases in the amount of Evans Blue dye at all airway levels. As with PGF2alpha, instillation of U-46619 produced a biphasic increase in R(L) and extravasation of Evans Blue dye. The potency of PGF2alpha in inducing these airway responses was about 1000 times less than U-46619. ICI-192,605 abolished both the immediate and the delayed increase in R(L) after PGF2alpha, and also blocked PGF2alpha-induced extravasation of Evans Blue dye. However, OKY-046 had no inhibitory effects on these responses. 4 We conclude that airflow obstruction and airway plasma exudation induced by instilled LTD4 is, in part, mediated via TxA2 generation and subsequent activation of TP-receptors. On the other hand, instilled PGF2alpha, while inducing similar responses, does so primarily by direct activation of TP receptors, rather than via TxA2 generation.