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

Abstract

1 Prostaglandin E₂ (PGE₂) relaxes circular smooth muscle of the rabbit isolated jugular vein at very low concentrations (mean pIC₅₀ against histamine-induced contraction = 9.34). This effect is not blocked by the EP₁-receptor antagonist, AH 6809 (2 μm). 2 From a group of prostaglandin E analogues examined, 16,16-dimethyl PGE₂, misoprostol, 11-deoxy PGE₂-1-alcohol and 11-deoxy PGE₁ were highly potent relaxant agents, whereas 17-phenyl-ω-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 PGE₁ 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-ω-trinor 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 μm 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 EP₁ 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.