Vasorelaxing Action of the Kynurenine Metabolite, Xanthurenic Acid: The Missing Link in Endotoxin-Induced Hypotension?

Frontiers in Pharmacology
Francesco FazioCarmine Vecchione

Abstract

The kynurenine pathway of tryptophan metabolism is activated by pro-inflammatory cytokines. L-kynurenine, an upstream metabolite of the pathway, acts as a putative endothelium-derived relaxing factor, and has been hypothesized to play a causative role in the pathophysiology of inflammation-induced hypotension. Here, we show that xanthurenic acid (XA), the transamination product of 3-hydroxykynurenine, is more efficacious than L-kynurenine in causing relaxation of a resistance artery, but fails to relax pre-contracted aortic rings. In the mesenteric artery, XA enhanced activating phosphorylation of endothelial nitric oxide synthase (NOS), and the relaxing action of XA was abrogated by pharmacological inhibition of NOS and endothelial-derived hyperpolarizing factor. Systemic injection of XA reduced blood pressure in mice, and serum levels of XA increased by several fold in response to a pulse with the endotoxin, lipopolysaccharide (LPS). LPS-induced hypotension in mice was prevented by pre-treatment with the kynurenine monooxygenase (KMO) inhibitor, Ro-618048, which lowered serum levels of XA but enhanced serum levels of L-kynurenine. UPF 648, another KMO inhibitor, could also abrogate LPS-induced hypotension. Our data identify X...Continue Reading

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Citations

Feb 15, 2019·Nature·Christopher P StanleyRoland Stocker
Jul 3, 2020·Frontiers in Immunology·Lijie ZhaiDerek A Wainwright
Mar 9, 2021·Pharmacology Research & Perspectives·Mohammad Al-Mahdi Al-KaragholiMessoud Ashina
Oct 16, 2020·Trends in Immunology·Elisa ProiettiGiada Mondanelli
Aug 11, 2021·Trends in Molecular Medicine·Niklas JoistenPhilipp Zimmer

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