Stimulatory effect of 8-Epi-PGF_2α, an F₂-isoprostane, on endothelin-1 release

8-Epi-prostaglandin F_2α(8-epi-PGF_2α) is an F₂-isoprostane produced in vivo by a cyclooxygenase-independent, free radical-catalyzed lipid peroxidation mechanism. It exhibits renal vasoconstrictor effects by binding to a receptor related to, but distinct from, that of thromboxane A₂(TxA₂). In cultured bovine aortic endothelial cells (BAECs), competitive binding assays using [³H]-8-epi-PGF_2αindicated the existence of two distinct binding sites. The K_dvalues were similar to those of cultured rat aortic smooth-muscle cells, suggesting that the high- and the low-affinity binding sites represent isoprostane and TxA₂receptors, respectively. 8-Epi-PGF_2αdose-dependently stimulated endothelin-1 (ET-1) secretion from BAECs. These increases were partially inhibited by a TxA₂receptor antagonist, consistent with the premise that isoprostanes and TxA₂recognize closely related receptors. The presence of specific binding sites for F₂-isoprostanes on endothelial cells widens the scope of the possible pathophysiologic significance of these eicosanoids, released during oxidant injury, to include alteration of endothelial cell biology. The release of ET-1 by 8-epi-PGF_2αmay help to explain the large increases in plasma and urinary concentrations for both ET-1 and 8-epi-PGF_2αin patients with hepatorenal syndrome.