DIFFERENTIAL ANTAGONISM OF AIRWAY CONTRACTILE RESPONSES TO PROSTAGLANDIN (PG)D-2 AND 9-ALPHA,11-BETA-PGF(2) BY ATROPINE, SK-AND-F-88046 ANDSQ-29,548 IN THE GUINEA-PIG
Dc. Underwood et al., DIFFERENTIAL ANTAGONISM OF AIRWAY CONTRACTILE RESPONSES TO PROSTAGLANDIN (PG)D-2 AND 9-ALPHA,11-BETA-PGF(2) BY ATROPINE, SK-AND-F-88046 ANDSQ-29,548 IN THE GUINEA-PIG, The Journal of pharmacology and experimental therapeutics, 268(1), 1994, pp. 304-310
PGD(2), the predominant prostanoid released from activated human lung
mast cells, is metabolized to 9 alpha,11 beta-PGF(2) by an 11-ketoredu
ctase. Both prostanoids contract mammalian airway smooth muscle. In th
e present study, aerosol administration of PGD(2) or 9 alpha,11 beta-P
GF(2) (five puffs of 10-50 mu g/ml) to anesthetized, spontaneously bre
athing guinea pigs produced significant increases in airway resistance
and decreases in dynamic lung compliance. The changes in airway resis
tance and dynamic lung compliance induced by 50 mu g/ml were reduced a
pproximately 60% and 25%, respectively, by pretreatment with atropine
(1 mg/kg, i.v., -10 min). Pretreatment with the TxA(2) receptor antago
nist SK&F 88046 (N,N'-bis[7-(3-chlorobenzene aminosulfonyl)-1 ,2,3,4-t
etrahydroisoquinolyl]disulfonylimide) (5 mg/kg, i.v., -10 min), nearly
abolished the changes in airway resistance and dynamic lung complianc
e that were elicited by both agonists. Pretreatment with a TxA(2) synt
hase 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, suggest
ing that these prostanoids did not provoke the release of TxA(2). In v
itro, PGD(2), 9 alpha,11 beta-PGF(2) and a TxA(2) mimic, U-44069, prod
uced concentration-dependent contractions of the guinea pig isolated t
rachea with pD(2)s of 6.4, 6.0 and 7.2, respectively. None of the conc
entration-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-P
GF(2) and 8.75 for U-44069. There was no significant difference in the
potencies of these antagonists against contractions elicited by the t
hree spasmogens. These data suggest that in vitro PGD(2) and 9 alpha,1
1 beta-PGF(2) elicit bronchospasm via the same mechanism, which involv
es activation of receptors that are sensitive to SK&F 88046 and SQ 29,
548. In vivo the same mechanism predominates, although there appears t
o be a contribution of a vagal reflex involving release of acetylcholi
ne.