Francesco Fazio, Albino Carrizzo, Luana Lionetto, Antonio Damato, Luca Capocci, Mariateresa Ambrosio, Giuseppe Battaglia, Valeria Bruno, Michele Madonna, Maurizio Simmaco, Ferdinando Nicoletti, Carmine 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 XA as a novel vasoactive compound and suggest that formation of XA is a key event in the pathophysiology of inflammation-induced hypotension.
Pharmacology, Toxicology and Pharmaceutical Science
4
11%
Medicine and Dentistry
3
8%
Nursing and Health Professions
1
3%
Other
4
11%
Unknown
12
32%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 01 May 2017.
All research outputs
#14,934,072
of 22,968,808 outputs
Outputs from Frontiers in Pharmacology
#5,255
of 16,241 outputs
Outputs of similar age
#184,711
of 310,759 outputs
Outputs of similar age from Frontiers in Pharmacology
#78
of 229 outputs
Altmetric has tracked 22,968,808 research outputs across all sources so far. This one is in the 32nd percentile – i.e., 32% of other outputs scored the same or lower than it.
So far Altmetric has tracked 16,241 research outputs from this source. They receive a mean Attention Score of 5.0. This one has gotten more attention than average, scoring higher than 60% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 310,759 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 37th percentile – i.e., 37% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 229 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 57% of its contemporaries.
