Differential antagonism of airway contractile responses to prostaglandin (PG)D2 and 9 alpha, 11 beta-PGF2 by atropine, SK&F 88046 and SQ 29,548 in the guinea pig.
PGD2, the predominant prostanoid released from activated human lung mast cells, is metabolized to 9 alpha, 11 beta-PGF2 by an 11-ketoreductase. Both prostanoids contract mammalian airway smooth muscle. In the present study, aerosol administration of PGD2 or 9 alpha, 11 beta-PGF2 (five puffs of 10-50 micrograms/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 micrograms/ml were reduced approximately 60% and 25%, respectively, by pretreatment with atropine (1 mg/kg, i.v., -10 min). Pretreatment with the TxA2 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 TxA2 synthase inhibitor, CGS 13080 (10 mg/kg, i.v., -10 min), had no effect on PGD2- or 9 alpha, 11 beta-PGF2-induced bronchoconstriction, suggesting that these prostanoids did not provoke the release of TxA2. In vitro, PGD2, 9 alpha, 11 beta-PGF2 and a TxA2 mimic, U-44069, produced concentration-dependent contractions of the guinea pig isolated trachea with pD2s of 6.4, 6.0 and 7.2, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Underwood
D C
DC
Department of Inflammation & Respiratory Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
Muccitelli
R M
RM
Luttmann
M A
MA
Hay
D W
DW
Torphy
T J
TJ
Wasserman
M A
MA
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016085:Bronchoconstrictor Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated; D006168:Guinea Pigs; D006834:Hydrazines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D015230:Prostaglandin D2 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000187:drug effects / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013449:Sulfonamides / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D016085:Bronchoconstrictor Agents; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C034339:SK&F 88046; D013449:Sulfonamides; D013928:Thromboxane A2; D001285:Atropine; C045749:SQ 29548; D015237:Dinoprost; D000109:Acetylcholine; D015230:Prostaglandin D2