Prostaglandin E2 (PGE2) mediates its effects on the blood vessels by binding to four E-prostanoid receptors, designated EP1, EP2, EP3 and EP4. EP1 and EP3 receptors are coupled to Ca2+ mobilisation and cAMP inhibition via Gq/Gi, respectively, and mediate vasoconstriction. EP2 and EP4 are coupled to stimulation of adenylyl cyclase via Gs proteins and mediate vasodilatation (1). Recent studies show that the EP4 receptor also couples to phosphatidylinositol-3-kinase (PI-3-K) that in turn activates Akt-kinase (PKB) (2). PKB can activate endothelial NO synthase. In the present study we wish to evaluate mouse aorta for isometric force measurements and determine if PGE2 causes vasodilatation by binding to the EP4 receptor, activating the PI-3K/Akt-dependent pathway and stimulating eNOS. Mice were humanely killed and aortic rings were prepared and mounted in an isometric force transducer. Phenylephrine (10-5M) followed by acetylcholine (10-6M) were added at the start of each experiment in order to test the viability of the media and the endothelium, respectively. All experiments were conducted in aerated (5% CO2 in air) Krebs-bicarbonate solution in the presence of the COX-inhibitor indomethacin (5×10-6M). Our results show that PGE2 has divergent effect on blood vessels because it is able to cause both dilatation and constriction. PGE2 constricted the mouse aortic rings in a concentration-dependent manner (EC50 (-log M) = 4.89 ± 0.06, n=8) and further constricted (p < 0.05) PE-preconstricted (6×10-8 M) aortic rings (EC50 (-log M) = 5.89 ± 0.06, n=4). In the presence of S18886, a TP-receptor antagonist (10-7 M), PGE2 (10-8 M to 10-6 M, n=6-7) relaxed PE-constricted (3×10-7 M) mouse aortic rings. L-NAME (10-4 M), a NO-syntase blocker, abolished the vasodilatation to PGE2 in PE-constricted segments (n=9). PGF2α also constricted the mouse aortic rings in a concentration-dependent manner (EC50 (-log M) = 5.03 ± 0.13, n=8). PGE2 caused no further constriction of PGF2α-constricted aortic rings indicating that PGE2 and PGF2α activate the same vasoconstrictor receptor (n=3). The constrictor effect of PGF2α was also abolished by S18886 (10-7 M, n=6). The current data indicate that PGE2 and PGF2α cause vasoconstriction in mouse aortic rings by activation of the TP-receptor. In the presence of a TP-receptor antagonist (S18886) PGE2 causes vasodilatation by stimulating NO synthesis.
University of Bristol (2005) J Physiol 567P, PC87
Poster Communications: Effect of PGE2 on isolated segments of mouse aorta
Hristovska, Ana-Marija; Rasmussen , Lasse; Skott, Ole; Jensen, Boye;
1. Dept. of Physiology and Pharmacology, University of Southern Denmark , Odense, Denmark.
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Where applicable, experiments conform with Society ethical requirements.