Response of rat thoracic aorta to F(2)-isoprostane metabolites.
This study was undertaken to investigate the vascular actions (contraction and relaxation) of the F(2)-isoprostane metabolites 15-keto-15-F(2t)-IsoP, 2,3-dinor-15-F(2t)-IsoP, and 2,3-dinor-5,6-dihydro -15-F(2t)-IsoP in comparison with 15-F(2t)-IsoP on the rat thoracic aorta. 15-keto-15-F(2t)-IsoP induced a vasoconstriction in a concentration-dependent manner with a pD(2) value of 5.80 +/- 0.05, whereas 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP had no effect. The parent compound 15-F(2t)-IsoP was more potent (pD(2) value: 6.46 +/- 0.1). Endothelium removal had no influence on the contraction to 15-keto-15-F(2t)-IsoP. GR32191 (a TP-receptor antagonist) concentration-dependently inhibited the contraction induced by 15-keto-15-F(2t)-IsoP, with a significant decrease in the E(max) values for GR32191 10(-7) M. Pretreatment with 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP induced no alteration of 15-F(2t)-IsoP concentration-response curves. In contrast, 15-keto-15-F(2t)-IsoP pretreatment competitively inhibited the response to 15-F(2t)-IsoP. When concentration ratios of EC(50) values were used, a Schild regression of this data was linear with a slope of 0.974 and a pA(2) value of 6.13. 15-keto-15-F(2t)-IsoP at high concentrations caused a weak concentration-dependent relaxation of rat aorta rings contracted with U46619 (3.10(-8) M) that was not modified in the absence of endothelium. In contrast, 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP induced no vasodilation. In conclusion, among the F(2)-isoprostane metabolites, 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP did not cause vasorelaxation or vasoconstriction on the rat thoracic aorta. In contrast, 15-keto-15-F(2t)-IsoP mediates contraction through activation of TP-receptors, probably as a partial agonist, and induces a weak endothelium-independent relaxation at high concentrations.
Cracowski
Jean-Luc
JL
Laboratoire de Pharmacologie, LSCPA EA2937, Faculté de Médecine de Grenoble, France. Jean-Luc.Cracowski@ujf-grenoble.fr
Camus
Laetitia
L
Durand
Thierry
T
Devillier
Philippe
P
Guy
Alexandre
A
Hardy
Gaëlle
G
Stanke-Labesque
Françoise
F
Rossi
Jean-Claude
JC
Bessard
Germain
G
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D028441:F2-Isoprostanes / Q000378:metabolism / Q000494:pharmacology*; D006538:Heptanoic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D011189:Potassium Chloride / Q000494:pharmacology; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011982:Receptors, Prostaglandin / Q000819:agonists; D017482:Receptors, Thromboxane / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
C433484:2,3-dinor-5,6-dihydro-15-F-isoprostane; D001713:Biphenyl Compounds; D028441:F2-Isoprostanes; D006538:Heptanoic Acids; D011448:Prostaglandin Antagonists; D011461:Prostaglandins F, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; C034671:prostaglandin F2alpha receptor; C075750:8-epi-prostaglandin F2alpha; C006326:fluprostenol; D011189:Potassium Chloride; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost; C060013:vapiprost