A novel inhibitory prostanoid receptor in piglet saphenous vein

doi:10.1016/0090-6980(94)90084-1

Prostaglandins

Volume 47, Issue 2, February 1994, Pages 151-168

Prostaglandins

https://doi.org/10.1016/0090-6980(94)90084-1 Get rights and content

Abstract

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 μM), in the presence of GR32191B (1μM), to block contractile TP-receptors. Under these conditions, PGD₂, PGE₂, PGF_2α, 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 30μM 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.

References (38)

Y. Sugimoto et al.
Cloning and expression of a cDNA for mouse prostaglandin E receptor EP₃-subtype
J. Biol. Chem.
(1992)
A. Honda et al.
Cloning and expression of a cDNA for mouse prostaglandin E receptor EP₂ subtype
J. Biol. Chem.
(1993)
P. Strong et al.
Prostanoid-induced inhibition of lipolysis in rat isolated adipocytes probable involvement of EP₃ receptors
Prostaglandins
(1992)
Y. Sugimoto et al.
Two isoforms of the EP₃-receptor with different carboxy-terminal domains
J. Biol. Chem.
(1993)
R. Reimer et al.
Effects of EP-receptor subtype specific agonists and other prostanoids on adenylate cyclase activity of duodenal epithelial cells
Prostaglandins
(1992)
I. Kennedy et al.
Studies on the characterisation of prostanoid receptors: a proposed classification
Prostaglandins
(1982)
R.A. Coleman et al.
Characterisation of the prostanoid receptors mediating contraction of guinea-pig isolated trachea
Prostaglandins
(1985)
R.A. Coleman et al.
Prostanoids and their receptors
T. Namba et al.
Alternative splicing of C-terminal tail of prostaglandin E receptor subtype EP₃ determines G-protein specificity
Nature
(1993)
Y. Gutman et al.
Mechanism of PGE and alpha adrenergic effects on release of catecholamines
Adv. Biosci.
(1979)

B.R. Creese et al.

The effects of prostaglandin E₂ on contractility and cyclic AMP levels of guinea-pig tracheal smooth muscle

Clin. Exp. Pharmacol. Physiol.

(1981)

H.L. Yeardley et al.

The effects of spasmolytic and spasmogenic prostanoids on cyclic AMP levels in human myometrium from pregnant donors

Br. J. Pharmacol.

(1993)

M.M. Jumblatt et al.

Prostaglandin E₂ effects on corneal endothelial cyclic adenosine monophosphate synthesis and cell shape are mediated by a receptor of the EP₂ subtype

Invest. Ophthalmol. Vis. Sci.

(1991)

A.A. Humbles et al.

Pharmacological characterisation of the prostanoid receptors in the rabbit isolated ear artery

Br. J. Pharmacol. Proc.

(1991)

R.A. Coleman et al.

Evidence for the existance of three subtypes of PGE₂ (EP) sensitive receptors in smooth muscle

Br. J. Pharmacol.

(1987)

R.A. Coleman et al.

New evidence with selective agonists and antagonists for the subclassification of PGE₂-sensitive (EP) receptors

Adv. Prostaglandin Thromboxane Leukotriene Res.

(1987)

J. Senior et al.

In vitro characterisation of prostanoid EP-receptors in the non-pregnant human myometrium

Br. J. Pharmacol.

(1991)

H. Yeardley et al.

A comparison of the inhibitory effects of prostanoid EP₂ receptor agonists and β₂-adrenoceptor agonists on human myometrium from pregnant donors

Br. J. Pharmacol. Proc.

(1992)

R. Garcia-Villar et al.

Evidence for the presence of AH13205 sensitive EP₂-prostanoid receptors in the pregnant baboon but not in the pregnant sheep myometrium near term

Biol. Reprod.

(1993)

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A novel inhibitory prostanoid receptor in piglet saphenous vein

Abstract

J. Biol. Chem.

J. Biol. Chem.

Prostaglandins

J. Biol. Chem.

Prostaglandins

Prostaglandins

Prostaglandins

Prostanoids and their receptors

Alternative splicing of C-terminal tail of prostaglandin E receptor subtype EP3 determines G-protein specificity

Nature

Mechanism of PGE and alpha adrenergic effects on release of catecholamines

Adv. Biosci.

The effects of prostaglandin E2 on contractility and cyclic AMP levels of guinea-pig tracheal smooth muscle

Clin. Exp. Pharmacol. Physiol.

The effects of spasmolytic and spasmogenic prostanoids on cyclic AMP levels in human myometrium from pregnant donors

Br. J. Pharmacol.

Prostaglandin E2 effects on corneal endothelial cyclic adenosine monophosphate synthesis and cell shape are mediated by a receptor of the EP2 subtype

Invest. Ophthalmol. Vis. Sci.

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Br. J. Pharmacol. Proc.

Evidence for the existance of three subtypes of PGE2 (EP) sensitive receptors in smooth muscle

Br. J. Pharmacol.

New evidence with selective agonists and antagonists for the subclassification of PGE2-sensitive (EP) receptors

Adv. Prostaglandin Thromboxane Leukotriene Res.

In vitro characterisation of prostanoid EP-receptors in the non-pregnant human myometrium

Br. J. Pharmacol.

A comparison of the inhibitory effects of prostanoid EP2 receptor agonists and β2-adrenoceptor agonists on human myometrium from pregnant donors

Br. J. Pharmacol. Proc.

Evidence for the presence of AH13205 sensitive EP2-prostanoid receptors in the pregnant baboon but not in the pregnant sheep myometrium near term

Biol. Reprod.

Alternative splicing of C-terminal tail of prostaglandin E receptor subtype EP₃ determines G-protein specificity

The effects of prostaglandin E₂ on contractility and cyclic AMP levels of guinea-pig tracheal smooth muscle

Prostaglandin E₂ effects on corneal endothelial cyclic adenosine monophosphate synthesis and cell shape are mediated by a receptor of the EP₂ subtype

Evidence for the existance of three subtypes of PGE₂ (EP) sensitive receptors in smooth muscle

New evidence with selective agonists and antagonists for the subclassification of PGE₂-sensitive (EP) receptors

A comparison of the inhibitory effects of prostanoid EP₂ receptor agonists and β₂-adrenoceptor agonists on human myometrium from pregnant donors

Evidence for the presence of AH13205 sensitive EP₂-prostanoid receptors in the pregnant baboon but not in the pregnant sheep myometrium near term