A range of prostanoid agonists were tested for activity on isolated ri
ng preparations of piglet saphenous vein. The selective TxA(2)-mimetic
(TP-receptor agonist), U-46619, contracted the preparation in a conce
ntration-related fashion. These contractions were in hibited by the TP
-receptor blocking drug, GR32191B, producing a pA(2) of 7.8 (slope 1.6
). Prostanoid-induced relaxant responses were studied on preparations
which had been pre contracted using an EC(60) concentration of phenyle
phrine (mean EC(60) = 0.97 mu M), in the presence of GR32191B (1 mu M)
, to block contractile TP-receptors. Under these conditions, PGD(2), P
GE(2), PGF(2 alpha), PGI(2), and U-46619, all caused concentration-rel
ated relaxation. PGE(2) was the most potent agonist (EC(50) = 0.23nM),
whereas, all of the other agonists were at least 1,000-fold weaker, p
roviding strong evidence for the presence of inhibitory EP-receptors,
The selective synthetic EP-agonists, sulprostone (EP(1)/Ep(3)) and AH1
3205X (EP(2)) were next tested for relaxant activity. While both compo
unds caused concentration-related relaxant activity, they were respect
ively 6,000 and 11,000-fold less potent than PGE(2). The potent TP-rec
eptou blocking drugs, AH22921X and AH23848B, were both weak antagonist
s of PGE(2) but not isoproterenol-induced relaxant responses of piglet
saphenous vein in a concentration-related fashion. These two compound
s had pA(2) values against PGE(2) of 5.3 and 5.4 respectively, with re
gression slopes not significantly different from unity. In contrast, n
either compound at a concentration of 30 mu M had any antagonist activ
ity against prostanoid-induced effects on guinea-pig fundus (EP(1)), r
abbit ear artery (EP(2)) or guinea-pig vas deferens (EP(3)). In conclu
sion, the piglet saphenous vein contains TP-receptors mediating smooth
muscle contraction, and a PGE(2)-specific (EP) receptor mediating rel
axation. The inhibitory EP-receptor does not appear to be of the EP(1)
, EP(2) or EP(3)-subtypes, and appears therefore to be a novel subtype
which we tentatively term EP(4), and the potent TP-receptor blocking
drugs, AH22921X and AH23848B, appear to be weak, but specific EP(4)-re
ceptor blocking drugs.