OP 13 The tryptophan metabolite kynurenine induces vasorelaxation in systemic maternal arteries – A new target for therapeutic intervention?

Introduction The important immunoregulatory role of Kynurenine (Kyn) pathway tryptophan metabolism in the placenta is well established. Activity of this pathway is reduced in pre-eclampsia. Recently Kyn was shown to relax blood vessels and reduce blood pressure in animal models [1] . In a small study of non-pregnant humans ( n  = 5), Kyn relaxed omental arteries; this was attenuated by Linopirdine (Lin; 10 μM), an inhibitor of type 7 voltage-gated potassium (Kv7) channels [2] . Objectives To determine if Kyn contributes to regulation of vascular tone in systemic resistance arteries in pregnancy. Materials and methods Omental resistance arteries ( 80 ). (3) Endothelial-intact arteries were treated with Lin 10 μM or vehicle (saline; 30mins) prior to U46619 constriction (EC 80 ) and Kyn dose–response (0.05–3 mM). Responses were compared by 2-way ANOVA with Bonferroni post-tests ( p Results Treatment with 1, 3 or 6 mM Kyn dose-dependently attenuated arterial constriction to U46619 ( N  = 4–8, p  = 0.003); greatest effect was observed at an intermediate U46619 dose of 10–7 M (change in constriction: control −0.19 ± 0.08 vs Kyn 6 mM −0.61 ± 0.13). Kyn induced relaxation of pre-constricted omental arteries ( N  = 7, p  = 0.032; 0.70 ± 0.11 vs. 0.35 ± 0.08). Treatment with Lin 10 μM had no effect on Kyn-induced relaxation ( N  = 5, p  = ns; 0.22 ± 0.12 vs. 0.17 ± 0.03). Conclusion This is the first study to demonstrate that Kyn has vasorelaxant effects on systemic resistance arteries in pregnancy. This supports our hypothesis that restoring Kyn pathway activity in pre-eclampsia could be a novel therapeutic target to attenuate maternal features of the disease. Kyn-induced relaxation was not inhibited by Lin 10 μM as previously reported outwith pregnancy, suggesting incomplete inhibition of Kv7 channels or an alternate compensatory mechanism.