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 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.

Pharmacological studies on prostanoid receptors in the rabbit isolated saphenous vein: a comparison with the rabbit isolated ear artery

“…The extremely high potency of PGE2 at EP-receptors, as in the rabbit saphenous vein, has been reported previously in tissues such as the rabbit jugular vein, hamster uterus and piglet saphenous vein (Lawrence & Jones, 1992;Yeardley et al, 1992;Coleman et al, 1994), and more recently, in the Published data from; t Coleman et al, 1994; rabbit ductus arteriosus (Smith et al, 1994). Furthermore, the agonist potency order in the rabbit saphenous vein is very similar to that found in the aforementioned tissues, all of which contain so called 'atypical' EP-receptors. Evidence for the existence of a fourth class of prostanoid EP-receptors has been strengthened by the recent cloning of two pharmacologically different subtypes.…”

Inhibition of vagally mediated gastric acid secretion by activation of central prostanoid EP3 receptors in urethane‐anaesthetized rats

“…Butaprost behaves as a selective EP2 receptor agonist with relatively low potency (agonist potencies: EP2> > > EP,) (Gardiner, 1986). In the present experiments, misoprostol and sulprostone (0.1, 0.3 (Dong et al, 1986; bition was pre- Lawrence et al, 1989;1992 (Ferreira et al, 1978;Kandasamy & Williams, 1982 In the central nervous suystem, EP3 receptor mRNA is highly expressed in brain regions such as the preoptic area, hypothalamus, locus coeruleus and raphe nuclei (Sugimoto et al, 1994). Administration of PGE2 into specific brain areas of the hypothalamus such as ventromedial hypothalamus and paraventricular nucleus of hypothalamus has been shown to inhibit stimulated gastric acid secretion (Barocelli et al, 1991).The paraventricular nucleus of the hypothalamus is a major site sending signals to the spinal sympathetic preganglionic neurones (Swanson & Sawchenko, 1983).…”

Identification of a prostanoid FP receptor population producing endothelium‐dependent vasorelaxation in the rabbit jugular vein

“…The vasorelaxant effect of PGF2. appears to be endothelium-dependent and has been attributed to stimulation of the prostanoid IP-receptor in the monkey cerebral arteries (Kawai & Ohhashi, 1991) and dog arteries (Toda et al, 1988), and IP-or EP2-receptors in human hand veins (Arner et al, 1994) (Giles et al, 1989;Lawrence & Jones, 1992 preparation, where removal of the endothelium only modestly affected its relaxant potency. PGE2 and PGD2, which respectively exhibit potent and moderate vasodilator properties in the RJuV (Giles et al, 1989;Milne et al, 1994), do not require an intact vacular endothelium to exert their relaxant responses.…”

“…In human isolated hand veins, the vasorelaxation to PGF2.. was partly endothelium-dependent (Arner et al, 1994). These PGF2,e,-mediated vasorelaxant effects were not attributed to stimulation of the FP-receptor but were suggested to occur by stimulation of the recognized relaxant prostanoid receptors such as the DP, EP2 and IP receptor subtypes (Giles et al, 1989;Nials et al, 1991;Lawrence & Jones, 1992) as well as an endothelium-derived relaxing factor.…”

“…The isolated external jugular vein of the rabbit was used because the rabbit was a readily available laboratory animal and relaxant EP, DP and IP receptors, but not FP receptors, have been reported in the vascular smooth muscle (Giles et al, 1989;; Lawrence & Jones, 1992). The present studies were performed with the endothelium of the rabbit jugular vein (RJuV) left intact or removed.…”