Leukotriene D4-andprostaglandin F2,,-induced airflow obstruction andairway plasma exudation inguinea-pig: role of thromboxane anditsreceptor

1 We studied theeffects ofa thromboxane A2receptor (TPreceptor) antagonist, ICI-192,605 (0.5mgkg-', i.v.) andaselective thromboxane (Tx)synthetase inhibitor, OKY-046(30mgkg-1, i.v.), onairway responses induced byleukotriene D4(LTD4; 0.2nmol)orprostaglandin F2a, (PGF2,; 20nmol) instilled viatheairways route toanaesthetized guinea-pigs. Foracomparison, airway responses toa TxA2-mimetic, U-46619 (0.02 nmol)werealsostudied. We measured bothlungresistance (RL)to monitor airflow obstruction, andextravasation ofEvansBluedyetoquantify airway plasma exudation. 2 Instilled LTD4intothetracheal lumeninduced animmediate peakandsubsequently persistent increase inRLandproduced alarge amountofextravasation ofEvansBluedyeatallairway levels. BothICI-192,605 andOKY-046significantly attenuated thepersistent increase inRLfollowing the immediate response andreduced LTD4-induced extravasation ofEvansBluedyeinthetrachea and proximal intrapulmonary airway. Instilled LTD4produced significant increases inimmunoreactive TxB2 inbronchoalveolar lavage fluid obtained 1.5minafter instillation ofLTD4. 3 Instilled PGF2.intothetracheal lumeninduced animmediate increase inRLwhichpeakedat approximately 15s.We alsoobserved adelayed sustained increase inRL,reaching asecond peakat approximately 4min.PGF2, produced small butsignificant increases intheamountofEvansBluedyeat allairway levels. AswithPGF,,instillation ofU-46619 produced a biphasic increase inRLand extravasation ofEvansBluedye.Thepotency ofPGFu, ininducing these airway responses wasabout 1000times less thanU-46619. ICI-192,605 abolished boththeimmediate andthedelayed increase inRL after PGF20, andalso blocked PGF2,-induced extravasation ofEvansBluedye.However, OKY-046had noinhibitory effects onthese responses. 4 We conclude thatairflow obstruction andairway plasma exudation induced byinstilled LTD4is, in part, mediated viaTxA2generation andsubsequent activation ofTP-receptors. On theother hand, instilled PGF2., while inducing similar responses, doessoprimarily bydirect activation ofTPreceptors, rather thanviaTxA2generation.