Response of rat thoracic aorta to F2-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.,,, 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 EC50 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.