Antagonism of the Thromboxane‐sensitive Contractile Systems of the Rabbit Aorta, Dog Saphenous Vein and Guinea‐pig Trachea

Abstract

1 The thromboxane-sensitive contractile systems in spirally-cut preparations of the rabbit aorta, dog saphenous vein and guinea-pig trachea have been compared. The full or partial agonist activities of a range of bicyclic ring analogues were found to be remarkably similar on the three preparations. In addition, EP 045, a prostanoid with a phenylsemicarbazone w-chain, blocked the action of both thromboxane A2 (TXA2) and the bicyclic ring analogues. Using 11,9-epoxymethano prostaglandin H2 as the agonist, linear Schild plots with slopes close to unity were obtained on each preparation; this suggests a competitive type of antagonism. 2 Analogues of prostaglandin D2 (PGD2), PGE2 and PGF2a also contracted the three smooth muscle preparations; those analogues containing a 16-p-halophenoxy residue were highly active. On the rabbit aorta, EP 045 completely blocked the contractile actions of these agonists, perhaps indicating a single type of prostanoid receptor in this tissue. On the dog saphenous vein PGD2, PGE2 and 15-methyl PGE2 exhibited relaxant activity when the tissue was partially contracted with either a thromboxane agonist or noradrenaline. On the guinea-pig trachea 16,16-dimethyl PGE2 and the 16-p-chlorophenoxy analogue of PGE2 were potent contractile agents whose action was not blocked by EP045. PGE2 and 15-methylPGE2 showed similar properties but exhibited relaxant activity with increasing concentrations in the organ bath. Our results indicate the presence of three types of prostanoid receptors in the guinea-pig trachea: thromboxane-and PGE-sensitive systems mediating contraction and a PGE-sensitive system mediating relaxation. 3 The similarity of the thromboxane-sensitive systems in the three smooth muscle preparations is discussed with particular reference to the differences in the equilibrium dissociation constants for EP 045.

Binding of a radioiodinated 13‐azapinane thromboxane antagonist to platelets: correlation with antiaggregatory activity in different species

“…Using these compounds, several groups have analysed the actions ofTXA2 on platelets and vascular as well as tracheal smooth muscles. These studies have suggested that TXA2 acts on a putative membrane receptor(s) to elicit its action, and based on different responsiveness of various systems to these compounds, multiplicity and differences in TXA2 receptors in various tissues and between species have been discussed (Lefer et al, 1980;Jones et al, 1982;Burke et al, 1983;Parise et al, 1984;Armstrong et al, 1985;Mais et al, 1985a).…”

“…These include 13-azaprostanoic acid (Le Breton et al, 1979), pinane thromboxane A2 (PTA2) (Nicolaou et al, 1979), AH-19437 ([km(Z),2P,5x]-methyl 7-[2-(4-morpholinyl)-3-oxo-5-(phenylmethoxy)cyclopentyl]-5-heptenoate, Coleman et al, 1981) and a 9,11-ethano-PGH2 analogue with a phenylsemicarbazone chain, EP-045, (Jones et al, 1982). ONO-I 1120 (9,1 1-dimethylmethano-I1,12-methano-16-phenyl)-13,14 -dihydro -13 -aza -15p-w-tetranor-TXA2) recently developed by Katsura et al (1983) has structural features of both 13-azaprostanoic acid and PTA2 (13-azapinane TXA2 derivative) and shows selective antagonism against STA2 and 11,9-epoxymethano-PGH2 in various systems (Katsura et al, 1983).…”

Prostaglandin endoperoxide analogues which are both thromboxane receptor antagonists and prostacyclin mimetics

“…They are prostanoid in nature with a ring system formally related to PGH2. They specifically block the stimulant actions of TXA2 and its stable mimetics on both vascular smooth muscle and platelets (Jones et al, 1982;Armstrong et al, 1985a). Primary Figure 1 Chemical structures of (a) 6a-carba prostaglandin 12, (b) iloprost (ZK 36,374), (c) EP 035, (d) EP 157, (e) EP 045 and (f) EP 092.…”

“…Bound and free radioligand were separated by rapid centrifugation after incubation for 4 min at room temperature. NCB-20 cells NCB-20 cells were cultured and homogenates and membrane suspensions prepared as described previously (Blair & MacDermot, 1981 Isolated smooth muscle preparations Spiral strips of rabbit aorta, dog saphenous vein and guinea-pig trachea were set up in conventional organ baths (8 ml) for isometric tension recording as described previously (Jones et al, 1982 In human PRP, AH 6809 counteracts PGD2-induced inhibition of aggregation whereas the action of PGI2 is slightly enhanced (Keery & Lumley, 1985 Figure 4). These concentrations are at least 300 fold higher than those used in the aggregation experiments and this provides additional evidence that thromboxane receptor block does not make a significnt contribution to the inhibitory action of EP 035 and EP 157.…”

Individual variations of prostanoid agonist responses in rabbit aorta: evidence for the independent regulation of prostanoid receptor subtypes

“…The apparent affinity of SQ29548 was approximately 10 fold less in the present study using the rabbit aorta. It has been consistently found that TP-receptor affinities for other thromboxane antagonists, e.g., EP045 and AH19437, in the rabbit aorta were approximately 10 fold less than values obtained in other tissues, e.g., rat aorta, dog saphenous vein, and guinea-pig trachea (Jones et al, 1982;Coleman et al, 1984). Since the dissociation constants for SQ29548 were not derived from a Schild analysis in the present study, it is not known whether a non-competitive interaction (revealed as a Schild plot slope different from 1) is causing an under-or overestimation of the actual receptor affinity.…”