A novel inhibitory prostanoid receptor in piglet saphenous vein.
A range of prostanoid agonists were tested for activity on isolated ring preparations of piglet saphenous vein. The selective TxA2-mimetic (TP-receptor agonist), U-46619, contracted the preparation in a concentration-related fashion. These contractions were inhibited by the TP-receptor blocking drug, GR32191B, producing a pA2 of 7.8 (slope = 1.6). Prostanoid-induced relaxant responses were studied on preparations which had been pre-contracted using an EC60 concentration of phenylephrine (mean EC60 = 0.97 microM), in the presence of GR32191B (1 microM), to block contractile TP-receptors. Under these conditions, PGD2, PGE2, PGF2 alpha, PGI2, and U-46619, all caused concentration-related relaxation. PGE2 was the most potent agonist (EC50 = 0.23nM), whereas, all of the other agonists were at least 1,000-fold weaker, providing strong evidence for the presence of inhibitory EP-receptors. The selective synthetic EP-agonists, sulprostone (EP1/EP3) and AH13205X (EP2), were next tested for relaxant activity. While both compounds caused concentration-related relaxant activity, they were respectively 6,000 and 11,000-fold less potent than PGE2. The potent TP-receptor blocking drugs, AH22921X and AH23848B, were both weak antagonists of PGE2 but not isoproterenol-induced relaxant responses of piglet saphenous vein in a concentration-related fashion. These two compounds had pA2 values against PGE2 of 5.3 and 5.4 respectively, with regression slopes not significantly different from unity. In contrast, neither compound at a concentration of 30 microM had any antagonist activity against prostanoid-induced effects on guinea-pig fundus (EP1), rabbit ear artery (EP2) or guinea-pig vas deferens (EP3). In conclusion, the piglet saphenous vein contains TP-receptors mediating smooth muscle contraction, and a PGE2-specific (EP) receptor mediating relaxation. The inhibitory EP-receptor does not appear to be of the EP1, EP2 or EP3-subtypes, and appears therefore to be a novel subtype which we tentatively term EP4, and the potent TP-receptor blocking drugs, AH22921X and AH23848B, appear to be weak, but specific EP4-receptor blocking drugs.
Department of Cardiovascular and Respiratory Pharmacology, Glaxo Group Research Ltd., Ware, Herts, U.K.
R A
RA
Coleman
S P
SP
Grix
S A
SA
Head
J B
JB
Louttit
A
A
Mallett
R L
RL
Sheldrick
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D006168:Guinea Pigs; D006538:Heptanoic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011453:Prostaglandins / Q000494:pharmacology; D011817:Rabbits; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D012501:Saphenous Vein / Q000187:drug effects / Q000378:metabolism*; D013552:Swine; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology
D001713:Biphenyl Compounds; D006538:Heptanoic Acids; D011450:Prostaglandin Endoperoxides, Synthetic; D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C046926:AH 23848; C060013:vapiprost