Contractile effects of 15-E 2t-isoprostane and 15-F 2t-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.