Prostaglandin D2-induced bronchoconstriction is mediated only in part by the thromboxane prostanoid receptor.
Prostaglandin D2 (PGD2) is a potent bronchoconstrictor, and is thought to have a role in the pathogenesis of asthma. PGD2 causes vasodilation acting via the prostaglandin (DP) receptor on vascular smooth muscle, and myocontraction acting via the thromboxane (TP) receptor on bronchial smooth muscle. To determine the relative contribution of these mechanisms we have studied the degree to which a potent TP receptor antagonist inhibits PGD2-induced bronchoconstriction. Twelve atopic asthmatic subjects underwent baseline PGD2 bronchial challenges to determine the cumulative concentration of PGD2 required to reduce forced expiratory volume in one second (FEV1) by 20%. At four subsequent randomized visits, subjects received this concentration of PGD2 90 min after dosing with placebo or 20, 50 or 100 mg of BAY u 3405, a potent competitive TP receptor antagonist. Serum was taken for drug assay at 90 min. After each dose of PGD2, FEV1 was measured for 30 min, and the area under the percentage fall in the FEV1/time curve (AUC) was calculated. The mean +/- SEM AUC for placebo was 414 +/- 68, and for the 20, 50 and 100 mg doses of BAY u 3405 was 169 +/- 33, 173 +/- 59 and 135 +/- 63, respectively. There were no significant differences between the AUCs for any of the drug doses, whilst all three doses were significantly different from placebo. The plateau response achieved with increasing doses of the antagonist suggests complete blockade of the TP receptor. These data demonstrate that thromboxane receptor blockade only partially inhibits the airway narrowing response to PGD2, and support the existence of a vascular component to PGD2-induced acute airway narrowing in asthma.
Johnston
S L
SL
Immunopharmacology Group, Southampton, General Hospital, UK.
Freezer
N J
NJ
Ritter
W
W
O'Toole
S
S
Howarth
P H
PH
D000328:Adult; D001249:Asthma / Q000503:physiopathology*; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects*; D002227:Carbazoles / Q000008:administration & dosage / Q000494:pharmacology*; D004311:Double-Blind Method; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D015230:Prostaglandin D2 / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000502:physiology; D017482:Receptors, Thromboxane / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D013931:Thromboxanes / Q000037:antagonists & inhibitors*
D002227:Carbazoles; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013931:Thromboxanes; C063119:ramatroban; D015230:Prostaglandin D2