EFFECTS OF A THROMBOXANE RECEPTOR ANTAGONIST ON PROSTAGLANDIN D(2) AND HISTAMINE-INDUCED BRONCHOCONSTRICTION IN MAN

Many prostanoids including are prostaglandin (PG) F2alpha and PGD2 are potent bronchoconstrictor agents. There is evidence to suggest that a irway thromboxane (TP) receptor may act as a common receptor for their bronchoconstrictor actions. We tested the hypothesis that inhaled pro staglandin (PG) D2-induced bronchoconstriction is mediated by interact ing with the TP receptor antagonist, ICI 192605, on the bronchoconstri ctor response to inhaled PGD2 in a double-blind, placebo-controlled an d crossed-over trial in normal subjects. The effect of ICI 192605 on h istamine induced bronchoconstriction served as control for non-specifi c bronchodilatory actions. The study had two phases; the first consist ed of two inhaled PGD2 challenge study days, and the second phase was that of inhaled histamine. Each study day was separated by at least a week. On each study day, the challenge tests were carried out 30 min a fter ingestion of 100 mg ICI 192605 or placebo. Doubling concentration s of agonist were given till more than 35% fall in post-diluent specif ic airway conductance (sGaw) occurred. The concentration needed to cau se a fall in a sGaw of 35% post-diluent value (PC35SGaw) was then dete rmined from linear interpolation of the log dose-response. Eight male subjects (median age 26, range 20-35 years) completed the study. ICI 1 92605 did not change baseline airway calibre 30 min after ingestion on either PGD2 or histamine study days. ICI 192605 significantly shifted the dose-response curve to inhaled PGD2 to the right by a median of 3 .4 fold (Wilcoxon rank sign test, P < 0.05). PC35sGaw PGD2 (geometric mean with 95% confidence limits) : placebo = 0.49 (0.13-1.85) mg ml-1; ICI 192605 = 1.60 (0.4-6.3) mg ml-1. In contrast, there was no change in PC35sGaw histamine [Placebo = 8.20 (2.95-22.4), ICI 192605 = 6.43 (3.24-12.6) mg ml-1]. The results showed that a TP receptor antagonist inhibited PGD2, but not histamine, induced bronchoconstriction in man . This supports the hypothesis that inhaled PGD2-induced bronchoconstr iction is mediated by interacting with airway TP receptor.