DIFFERENTIAL ANTAGONISM OF AIRWAY CONTRACTILE RESPONSES TO PROSTAGLANDIN (PG)D-2 AND 9-ALPHA,11-BETA-PGF(2) BY ATROPINE, SK-AND-F-88046 AND SQ-29,548 IN THE GUINEA-PIG

PGD(2), the predominant prostanoid released from activated human lung mast cells, is metabolized to 9 alpha,11 beta-PGF(2) by an 11-ketoreductase. Both prostanoids contract mammalian airway smooth muscle. In the present study, aerosol administration of PGD(2) or 9 alpha,11 beta-PGF(2) (five puffs of 10-50 mu g/ml) to anesthetized, spontaneously breathing guinea pigs produced significant increases in airway resistance and decreases in dynamic lung compliance. The changes in airway resistance and dynamic lung compliance induced by 50 mu g/ml were reduced approximately 60% and 25%, respectively, by pretreatment with atropine (1 mg/kg, i.v., -10 min). Pretreatment with the TxA(2) receptor antagonist SK&F 88046 (N,N'-bis[7-(3-chlorobenzene aminosulfonyl)-1 ,2,3,4-tetrahydroisoquinolyl]disulfonylimide) (5 mg/kg, i.v., -10 min), nearly abolished the changes in airway resistance and dynamic lung compliance that were elicited by both agonists. Pretreatment with a TxA(2) synthase inhibitor, CGS 13080 (10 mg/kg, i.v., -10 min), had no effect on PGD(2-) or 9 alpha,11 beta-PGF(2-)induced bronchoconstriction, suggesting that these prostanoids did not provoke the release of TxA(2). In vitro, PGD(2), 9 alpha,11 beta-PGF(2) and a TxA(2) mimic, U-44069, produced concentration-dependent contractions of the guinea pig isolated trachea with pD(2)s of 6.4, 6.0 and 7.2, respectively. None of the concentration-response curves were altered by atropine (10 mu M), but they were shifted significantly to the right by SK&F 88046 (3 mu M), With pK(B) values of 6.9 for PGD(2), 7.0 for 9 alpha,11 beta-PGF(2) and 6.6 for U-44069 or another TxA(2) receptor antagonist, SQ 29548 (10 nM-1 mu M) with pA(2) values of 8.19 for PGD(2), 8.56 for 9 alpha,11 beta-PGF(2) and 8.75 for U-44069. There was no significant difference in the potencies of these antagonists against contractions elicited by the three spasmogens. These data suggest that in vitro PGD(2) and 9 alpha,11 beta-PGF(2) elicit bronchospasm via the same mechanism, which involves activation of receptors that are sensitive to SK&F 88046 and SQ 29,548. In vivo the same mechanism predominates, although there appears to be a contribution of a vagal reflex involving release of acetylcholine.