Characterization of prostanoid relaxant/inhibitory receptors (ψ) using a highly selective agonist, TR4979

1 Prostaglandin E2 (PGE2) relaxes circular smooth muscle of the rabbit isolated jugular vein at very low concentrations (mean pICm against histamine-induced contraction = 9.34). This effect is not blocked by the EP,-receptor antagonist, AH 6809 (2 JM). 2 From a group of prostaglandin E analogues examined, 16,16-dimethyl PGE2, misoprostol, 1-deoxy PGE2-I-alcohol and 1 1-deoxy PGE, were highly potent relaxant agents, whereas 17-phenyl-w-trinor PGE2, MB 28767 and butaprost had low potency and sulprostone and oxoprostol were virtually inactive.3 Comparison of the jugular vein data with published data for inhibitory agonist potencies on the cat trachea (EP2 preparation) and the field-stimulated guinea-pig vas deferens (EP3) indicates that the EP-receptor in the rabbit jugular vein is closest to the EP2 subtype. However, the correlation is not entirely convincing. For example, butaprost, 16,16-dimethyl PGE2 and 11-deoxy PGEI are of similar potency on the cat trachea, whereas butaprost is about 300 times less potent than the other two analogues on the jugular vein. The existence of more than one EP2-receptor appears possible. 4 It was felt that the activity of butaprost required further investigation in view of the claim that it is a specific EP2-receptor agonist. We have shown that butaprost has very low inhibitory activity on the guinea-pig vas deferens, a very sensitive EP3-receptor containing preparation. However, on the chick ileum, the original EP3 preparation, butaprost showed potent contractile activity (pEC25 -8.0). In addition, its maximum response was lower than that of PGE2; lower maxima were also found for sulprostone, MB 28767 and oxoprostol, but not for ICI 80205, 16,16-dimethyl PGE2 and 17-phenyl-wtrinor PGE2. The maximal response to a combination of either sulprostone and butaprost or sulprostone and PGE2 was similar to that achieved by PGE2 alone. Analysis of the interaction between sulprostone and PGE2 appears to exclude a partial agonist action for sulprostone. Furthermore neither sulprostone nor butaprost appear to have inhibitory activity on the ileum. AH 6809 at 2 pM produced only a small shift of the PGE2 log concentration-response curve. 5 It is likely that contraction of the longitudinal smooth muscle of the chick ileum is mediated by (at least) two EP-receptor subtypes; activation of only one receptor system does not induce the maximum response (i.e. the acetylcholine maximum) of the preparation. One receptor could be an EP3 subtype, at which sulprostone exerts a selective agonist action. The other receptor is unlikely to be an EP, subtype, because of the high agonist potency of butaprost, the low agonist potency of iloprost, and the low antagonist potency of AH 6809. An alternative hypothesis is that the chick ileum contains a novel EP-receptor subtype in addition to an EP3-receptor.

Section: Discussionmentioning

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Investigation of the prostaglandin E (EP‐) receptor subtype mediating relaxation of the rabbit jugular vein

Lawrence

Jones

1992

“…The selective EP2-receptor agonists, 1 1-deoxy PGEI (Lawrence et al, 1992), butaprost (Gardiner, 1986) and AH 13205 (Nials et al, 1993) also inhibited chemotaxis, giving maximal inhibitions of 43.8 +7.9% (n=3), 65.2±6.2% (n=5) and 61.9 ± 2.7% (n = 3), respectively at concentrations of 1OyM (Figure 2a). Taking the maximal effect of PGE2 at 10 $M as 100% response, apparent EC5&s of 106.4±63 nM, 140.9±64.7 nM and 1.58±0.73 pM were determined for butaprost, 1 1-deoxy PGEI and AH 13205, respectively.…”

Section: Inhibition Of Chemotaxis By Selective Ep Agonistsmentioning

confidence: 99%

Investigation of the inhibitory effects of PGE₂ and selective EP agonists on chemotaxis of human neutrophils

Armstrong

1995

104

1 The aims of this study were to investigate the inhibitory effects of prostaglandin E2 (PGE2) on chemotaxis of N-formyl-methionyl-leucine-phenylalaiine (FMLP)-stimulated human neutrophils, and to test the hypothesis that cyclic AMP is the second messenger involved. For this purpose, the inhibitory effect of selective EP agonists, and the modulatory effects of the adenylate cyclase inhibitor, SQ 22536, the protein kinase A (PKA) inhibitors H-89 and Rp-cAMPS, and the type IV phosphodiesterase (PDE) inhibitors, rolipram and Ro20-1724 have been examined. 2 Chemotaxis has been measured using blindwell chambers. When human neutrophils were stimulated with FMLP (100 nM), PGE2 inhibited chemotaxis in a concentration-dependent manner (0.01-10 Mm), with an EC50 of 90+24.5 nm, a maximum effect ranging from 45-75% and a mean inhibition of 64.5 ± 2.4%.

“…In general, conclusions must be drawn on the basis of results obtained from various combinations of receptor selective compounds, and a process of elimination. To date, butaprost (TR4979) (Gardiner et al, 1986) appears to be the most selective agonist for the study of EP-receptors in that it shows high potency and selectivity at the EP2-receptor subtype, with little or no activity for the EP1-or EP3-receptors. Other PGE analogues such as sulprostone, rioprostil and misoprostol are useful but show activity at two EP-receptor types.…”

Section: Introductionmentioning

confidence: 99%

In vitro characterization of prostanoid EP‐receptors in the non‐pregnant human myometrium

Senior

Marshall

Sangha

et al. 1991

Postgraduate Studies in Pharmacology, University of Bradford, Bradford, BD7 lDP and *The Royal Infirmary, Bradford, BD9 6RJ1 Prostaglandin receptors of the PGE type have been characterized in the non-pregnant human myometrium in vitro according to the scheme of Coleman et al. (1984) by use of the agonists PGE2, sulprostone, rioprostil, AY23626, butaprost, misoprostol, 16,16-dimethylprostaglandin E2, enprostil and iloprost, and, the antagonist AH6809. 2 All prostanoids tested were active in non-pregnant human myometrium either as stimulators and/or inhibitors of spontaneous activity or both. Biphasic responses to PGE2 indicate that at least two receptor types of the EP-receptor exist, one mediating relaxation and the other mediating contraction. 3 Further evidence for the EP-receptor mediating excitation and relaxation was provided by the action of the EP2-/EP3-receptor selective prostanoids rioprostil, AY23626 and misoprostol, and the EP1-/EP2-receptor selective agonist 16,16-dimethylprostaglandin E2. 4 Butaprost, an EP2-receptor selective agonist, produced potent inhibition of spontaneous activity in the tissue which was generally longer-lasting than that evoked by the natural prostanoid PGE2. 5 The EP1-/EP3-receptor selective agonist sulprostone and the EP3-receptor agonist enprostil produced potent contractile responses supporting the presence of contractile EP3-receptors in the non-pregnant human myometrium in vitro.6 The EP,-/IP-receptor selective agonist, iloprost, produced mixed responses in non-pregnant human myometrium. The contractile response was inhibited by the EP,-receptor antagonist AH6809. However, responses to the EP1-/EP3-receptor selective agonist sulprostone were unaffected by AH6809 which may indicate that only a small population of EP1-receptors is present.