Evidence for thromboxane receptor mediated contraction of guinea-pig and human airways in vitro by prostaglandin (PG) D2, 9 alpha,11 beta-PGF2 and PGF2 alpha.
The rank orders of potency of prostaglandin D2, prostaglandin F2 alpha, 9 alpha,11 beta-prostaglandin F2 and the stable thromboxane A2 mimetics U-46619 and ONO-11113 were determined in guinea-pig trachea and human bronchus in vitro. In both tissues the thromboxane mimetics were markedly more potent than the other prostanoids with EC50 values in the nanomolar range. The prostanoid antagonists BW-245C, EP-092 and GR-32191 attenuated the contractile responses to all of the prostanoid agonists and TXA2 mimetics tested in guinea-pig tracheal spirals, although agonist selectivity was seen. Contractile responses to methacholine in the guinea-pig trachea were unaffected by any of the antagonists employed. BW-245C antagonised the effects of all prostanoid agonists tested in human bronchial spirals, the pA2 values obtained were similar to those seen in the guinea-pig trachea when U-46619 and 9 alpha,11 beta-PGF2 were employed as the agonists. However, significant differences were found between the two tissues when PGD2 and PGF2 alpha were tested against BW-245C. EP-092 produced pA2 values against prostanoid agonists in the human bronchus similar to those seen in the guinea-pig trachea, as did GR-32191. It is concluded that whilst the contractile responses of guinea-pig and human airways smooth muscle to prostaglandin D2, and the other prostanoids are mediated predominantly via thromboxane (TP) receptors, it can be inferred that other receptor populations may contribute to the contractile response. The presence of these minor subpopulations may account for the agonist selectivity seen both within and between tissues from different species.
Featherstone
R L
RL
Clinical Pharmacology and Medicine I, Southampton General Hospital.
Robinson
C
C
Holgate
S T
ST
Church
M K
MK
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D001980:Bronchi / Q000502:physiology* / Q000648:ultrastructure; D015237:Dinoprost / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D006827:Hydantoins / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D015230:Prostaglandin D2 / Q000494:pharmacology*; D011465:Prostaglandins, Synthetic / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000502:physiology*; D017482:Receptors, Thromboxane; D013931:Thromboxanes / Q000037:antagonists & inhibitors; D014132:Trachea / Q000502:physiology* / Q000648:ultrastructure
D001713:Biphenyl Compounds; D006538:Heptanoic Acids; D006827:Hydantoins; D011465:Prostaglandins, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013931:Thromboxanes; C030669:BW 245C; C045332:EP 092; D015237:Dinoprost; C060013:vapiprost; D015230:Prostaglandin D2