Effect of a thromboxane receptor antagonist on PGD2- and allergen-induced bronchoconstriction.
In this study we investigated the effect of the selective and potent thromboxane A2 (TxA2) receptor antagonist GR32191 on smooth muscle contraction induced by the TxA2 analogue U46619, prostaglandin (PG) D2, PGF2 alpha, and methacholine (MCh) in guinea pig airways in vitro and the airways response provoked by inhaled PGD2 and MCh in asthmatic subjects in vivo. GR32191 antagonized competitively the contractile responses of all three prostanoids to a similar degree but had no effect on MCh-induced contractions. In asthmatic subjects GR32191, in a single oral dose of 80 mg, did not affect base-line airway caliber or MCh-induced broncho-constriction but caused significant inhibition of PGD2-induced bronchoconstriction, displacing the concentration-response curves to the right by greater than 10-fold. The effect of the same oral dose of GR32191 on allergen-induced immediate bronchoconstriction was subsequently investigated in allergic asthmatic subjects. In individual subjects, GR32191 inhibited to varying degrees the overall bronchoconstrictor response, with the maximum effect occurring between 10 and 30 min after allergen challenge. These studies suggest that prostanoids contribute to the immediate bronchoconstriction induced by inhaled allergen in allergic asthmatics, and that this effect is mediated by stimulation of a thromboxane receptor.
Beasley
R C
RC
Immunopharmacology Group, Southampton General Hospital, United Kingdom.
Featherstone
R L
RL
Church
M K
MK
Rafferty
P
P
Varley
J G
JG
Harris
A
A
Robinson
C
C
Holgate
S T
ST
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000293:Adolescent; D000328:Adult; D000818:Animals; D001249:Asthma / Q000503:physiopathology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects*; D015237:Dinoprost / Q000494:pharmacology*; D006168:Guinea Pigs; D006538:Heptanoic Acids / Q000494:pharmacology*; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008688:Methacholine Compounds / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*
D001713:Biphenyl Compounds; D006538:Heptanoic Acids; D008688:Methacholine Compounds; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D006632:Histamine; D015237:Dinoprost; C060013:vapiprost; D015230:Prostaglandin D2