Interference of WEB 2086 and BN 52021 with Paf-induced effects on guinea-pig trachea

1. The thienotriazolodiazepine WEB 2086 and the gingkolide BN 52021 have been evaluated as antagonists of Paf-acether (Paf) by studying their effects on Paf-induced relaxation and Paf-induced prostaglandin E₂ (PGE₂) production in histamine-contracted guinea-pig tracheal preparations. 2. Relaxation induced by Paf 4 μM in histamine-contracted guinea-pig tracheal preparations was 39.67 ± 3.5% (n = 30). At the same concentration, Paf significantly increased PGE₂ production from histamine-contracted guinea-pig tracheal preparations. 3. WEB 2086 inhibited in a dose-related manner (IC₅₀ = 21.2 nM) the relaxant effect induced by Paf and, at 1 μM, suppressed Paf-induced release of PGE₂. 4. BN 52021 100 μM inhibited to about 60% Paf-induced relaxation of histamine-contracted guinea-pig tracheal preparations, but completely abolished Paf-induced increase in PGE₂. 5. Both antagonists had no effects on relaxations induced by arachidonic acid 10 μM or PGE₂ 0.1-1 μM in histamine-contracted guinea-pig tracheal preparations. 6. The results are consistent with the presence of specific Paf receptors in guinea-pig trachea and indicate that a relaxant prostanoid, namely PGE₂, at least partially mediates Paf-induced relaxation in this experimental model.