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Vasorelaxing Action of the Kynurenine Metabolite, Xanthurenic Acid: The Missing Link in Endotoxin-Induced Hypotension?
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 h...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410560/ https://www.ncbi.nlm.nih.gov/pubmed/28507519 http://dx.doi.org/10.3389/fphar.2017.00214 |
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author | Fazio, Francesco Carrizzo, Albino Lionetto, Luana Damato, Antonio Capocci, Luca Ambrosio, Mariateresa Battaglia, Giuseppe Bruno, Valeria Madonna, Michele Simmaco, Maurizio Nicoletti, Ferdinando Vecchione, Carmine |
author_facet | Fazio, Francesco Carrizzo, Albino Lionetto, Luana Damato, Antonio Capocci, Luca Ambrosio, Mariateresa Battaglia, Giuseppe Bruno, Valeria Madonna, Michele Simmaco, Maurizio Nicoletti, Ferdinando Vecchione, Carmine |
author_sort | Fazio, Francesco |
collection | PubMed |
description | 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 XA as a novel vasoactive compound and suggest that formation of XA is a key event in the pathophysiology of inflammation-induced hypotension. |
format | Online Article Text |
id | pubmed-5410560 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-54105602017-05-15 Vasorelaxing Action of the Kynurenine Metabolite, Xanthurenic Acid: The Missing Link in Endotoxin-Induced Hypotension? Fazio, Francesco Carrizzo, Albino Lionetto, Luana Damato, Antonio Capocci, Luca Ambrosio, Mariateresa Battaglia, Giuseppe Bruno, Valeria Madonna, Michele Simmaco, Maurizio Nicoletti, Ferdinando Vecchione, Carmine Front Pharmacol Pharmacology 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 XA as a novel vasoactive compound and suggest that formation of XA is a key event in the pathophysiology of inflammation-induced hypotension. Frontiers Media S.A. 2017-05-01 /pmc/articles/PMC5410560/ /pubmed/28507519 http://dx.doi.org/10.3389/fphar.2017.00214 Text en Copyright © 2017 Fazio, Carrizzo, Lionetto, Damato, Capocci, Ambrosio, Battaglia, Bruno, Madonna, Simmaco, Nicoletti and Vecchione. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Fazio, Francesco Carrizzo, Albino Lionetto, Luana Damato, Antonio Capocci, Luca Ambrosio, Mariateresa Battaglia, Giuseppe Bruno, Valeria Madonna, Michele Simmaco, Maurizio Nicoletti, Ferdinando Vecchione, Carmine Vasorelaxing Action of the Kynurenine Metabolite, Xanthurenic Acid: The Missing Link in Endotoxin-Induced Hypotension? |
title | Vasorelaxing Action of the Kynurenine Metabolite, Xanthurenic Acid: The Missing Link in Endotoxin-Induced Hypotension? |
title_full | Vasorelaxing Action of the Kynurenine Metabolite, Xanthurenic Acid: The Missing Link in Endotoxin-Induced Hypotension? |
title_fullStr | Vasorelaxing Action of the Kynurenine Metabolite, Xanthurenic Acid: The Missing Link in Endotoxin-Induced Hypotension? |
title_full_unstemmed | Vasorelaxing Action of the Kynurenine Metabolite, Xanthurenic Acid: The Missing Link in Endotoxin-Induced Hypotension? |
title_short | Vasorelaxing Action of the Kynurenine Metabolite, Xanthurenic Acid: The Missing Link in Endotoxin-Induced Hypotension? |
title_sort | vasorelaxing action of the kynurenine metabolite, xanthurenic acid: the missing link in endotoxin-induced hypotension? |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410560/ https://www.ncbi.nlm.nih.gov/pubmed/28507519 http://dx.doi.org/10.3389/fphar.2017.00214 |
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