Abstract 624: Resolvin E1 Inhibits Thromboxane-Induced Contraction of Rat Aorta and Human Pulmonary Artery

Abstract

Thromboxane is a vasoactive omega-6-derived lipid implicated in hypertension. Omega-3 fatty acid derivatives including resolvin (Rv) E1 have important roles in the resolution of inflammation, but their ability to mediate vasomotor activity is unknown. We assessed whether RvE1 modulates contraction of rat thoracic aorta and human pulmonary artery (HPA) in vitro. Rats were culled by CO2 inhalation and cervical dislocation, and the thoracic aorta was removed. HPA were obtained with informed consent from lung tissue of surgical patients at Southampton General Hospital. Segments of aorta or HPA were incubated in DMEM-F12 with or without RvE1 (10 nM, 100 nM or 300 nM) for 1 or 24 hours, and then mounted on a wire myograph. Mounted segments were bathed at 37[[Unable to Display Character: ]]C in Kreb’s buffer, gassed (95%/5% O2/CO2) and set to 1.5 g of baseline tension. Functional integrity was confirmed by a contractile response to 125 mM KPSS. After washing to restore baseline tension, a cumulative concentration-response curve was defined to the stable thromboxane A2 mimetic U46619 (1 nM - 1 μM). Contractions are expressed as percent of KPSS response and differences determined by two-way ANOVA and by pairwise comparisons. In rat aorta, treatment with RvE1 (10 nM) significantly shifted the U46619 curve rightwards, increasing the EC50 value 13-fold from 0.13 μM to 1.75 μM after 1 hour (n=5), and 4-fold from 0.093 μM to 0.41 μM after 24 hours (n=5). In contrast, 300 nM RvE1 caused no significant change in EC50 (1 hour 0.11 μM; 24 hours 0.097 μM, n=5). In HPA segments, RvE1 (10 nM, 1 hour) increased the U46619 EC50 value 7-fold from 0.0079 μM to 0.054 μM (n=3), with a preliminary experiment suggesting a similar outcome after 24 hours. Higher concentrations of RvE1 had no significant effect, suggesting the relaxant action of RVE1 has a bell-shaped response curve. In preliminary experiments, RvE1 inhibited U-46619 contractions of bronchiolar airways from the same human donors. Resolvin E1 is known for its immunomodulatory actions on leukocytes and also inhibits U46619-induced aggregation of platelets, but our results are the first evidence that this pro-resolution mediator can also inhibit contractions of intact vasculature from rat and human lung induced by a thromboxane mimetic.