title: Contractile effects of 15-E2t-isoprostane and 15-F2t-isoprostane on chicken embryo ductus arteriosus.
abstract: Isoprostanes (IsoPs) are prostaglandin (PG)-like compounds produced nonenzymatically by free radical-catalyzed peroxidation of arachidonate. Cyclooxygenase-derived PGs play a major role in ductus arteriosus (DA) homeostasis but the putative role of IsoPs has not been studied so far. We investigated, using wire myography, the vasoactive effects of 15-E(2t)-IsoP and 15-F(2t)-IsoP in the chicken embryo DA, pulmonary artery (PA) and femoral artery (FA). 15-E(2t)-IsoP and 15-F(2t)-IsoP contracted DA, PA, and FA rings in a concentration-dependent manner. 15-E(2t)-IsoP was equally efficacious (mean±SE E(max)=1.25±0.06 mN/mm) as and more potent (-log of molar concentration producing 50% of E(max)=pEC(50)=7.00±0.04) than the thromboxane-prostanoid (TP) receptor agonist U46619 (E(max)=1.49±0.11 mN/mm; pEC(50)=6.48±0.05) in contracting chicken DA (pulmonary side). 15-F(2t)-IsoP was less potent (pEC(50)=5.74±0.11) and less efficacious (E(max)=0.96±0.11) than U46619. Concentration-dependent contractions to 15-E(2t)-IsoP and U46619 in DA rings were competitively inhibited by the TP receptor antagonist SQ29548 (0.1 μM to 10 μM) with no decrease in the E(max) values. SQ29548 also inhibited concentration-dependent contraction to 15-F(2t)-IsoP but this inhibition was associated with a decrease in E(max). Pre-incubation of DA rings with 15-F(2t)-IsoP inhibited responses to U46619 and, in vessels contracted with U46619 (1 μM), 15-F(2t)-IsoP (>1 μM) evoked a relaxant response. Enzyme immunoassay did not show a measurable release of 15-F(2t)-IsoP by DA rings. In conclusion, 15-E(2t)-IsoP is a potent and efficacious constrictor of chicken DA, acting through TP receptors. In contrast, 15-F(2t)-IsoP is probably acting as a partial agonist at TP receptors. We speculate that IsoPs play a role in the control of chicken DA tone and could participate in its closure.
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center (MUMC+), School for Oncology and Developmental Biology (GROW), Maastricht, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: van der Sterren
authors.forename: Eduardo
authors.initials: E
authors.lastname: Villamor
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D002642:Chick Embryo; D015237:Dinoprost / Q000031:analogs & derivatives; D004373:Ductus Arteriosus / Q000187:drug effects / Q000196:embryology*; D005263:Femoral Artery / Q000187:drug effects*; D028421:Isoprostanes / Q000378:metabolism*; D009119:Muscle Contraction / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D009213:Myography / Q000379:methods; D018384:Oxidative Stress; D011453:Prostaglandins / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000037:antagonists & inhibitors; D017482:Receptors, Thromboxane / Q000819:agonists / Q000037:antagonists & inhibitors; D014661:Vasoconstriction / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000378:metabolism
chemical_list: D028421:Isoprostanes; D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; C075750:8-epi-prostaglandin F2alpha; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost