Ra. Lawrence et Rl. Jones, INVESTIGATION OF THE PROSTAGLANDIN-E (EP-) RECEPTOR SUBTYPE MEDIATINGRELAXATION OF THE RABBIT JUGULAR-VEIN, British Journal of Pharmacology, 105(4), 1992, pp. 817-824
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 t
he EP1-receptor antagonist, AH 6809 (2-mu-M). 2 From a group of prosta
glandin E analogues examined, 16,16-dimethyl PGE2, misoprostol, 11-deo
xy PGE2-1-alcohol and 11-deoxy PGE1 were highly potent relaxant agents
, whereas 17-phenyl-omega-trinor PGE2, MB 28767 and butaprost had low
potency and sulprostone and oxoprostol were virtually inactive. 3 Comp
arison of the jugular vein data with published data for inhibitory ago
nist potencies on the cat trachea (EP2 preparation) and the field-stim
ulated guinea-pig vas deferens (EP3) indicates that the EP-receptor in
the rabbit jugular vein is closest to the EP2 subtype. However, the c
orrelation is not entirely convincing. For example, butaprost, 16,16-d
imethyl PGE2 and 11-deoxy PGE1 are of similar potency on the cat trach
ea, whereas butaprost is about 300 times less potent than the other tw
o analogues on the jugular vein. The existence of more than one EP2-re
ceptor appears possible. 4 It was felt that the activity of butaprost
required further investigation in view of the claim that it is a speci
fic EP2-receptor agonist. We have shown that butaprost has very low in
hibitory activity on the guinea-pig vas deferens, a very sensitive EP3
-receptor containing preparation. However, on the chick ileum, the org
inal EP3 preparation, butaprost showed potent contractile activity (pE
C25 approximately 8.0). In addition, its maximum response was lower th
an that of PGE2; lower maxima were also found for sulprostone, MB 2876
7 and oxoprostol, but not for ICI 80205, 16,16-dimethyl PGE2 and 17-ph
enyl-omega-trinor PGE2. The maximal response to a combination of eithe
r sulprostone and butaprost or sulprostone and PGE2 was similar to tha
t achieved by PGE2 alone. Analysis of the interaction between sulprost
one and PGE2 appears to exclude a partial agonist action for sulprosto
ne. Furthermore neither sulprostone nor butaprost appear to have inhib
itory activity on the ileum. AH 6809 at 2-mu-M produced only a small s
hift of the PGE2 log concentration-response curve. 5 It is likely that
contraction of the longitudinal smooth muscle of the chick ileum is m
ediated by (rat least) two EP-receptor subtypes; activation of only on
e receptor system does not induce the maximum response (i.e. the acety
lcholine maximum) of the preparation. One receptor could be an EP3 sub
type, at which sulprostone exerts a selective agonist action. The othe
r receptor is unlikely to be an EP1 subtype, because of the high agoni
st potency of butaprost, the low agonist potency of iloprost, and the
low antagonist potency of AH 6809. An alternative hypothesis is that t
he chick ileum contains a novel EP-receptor subtype in addition to an
EP3-receptor.