Role of kynurenin and its derivatives in cardiac arrhythmias

Rudzite, Vera; Sileniece, G.; Jirgenson, J. B.

doi:10.1007/bf00840806

Cited by 1 publication

(1 citation statement)

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“…The recent demonstration that XA is biologically active, interacts with a not-yet identified G-protein-coupled receptor, and its plasma levels are largely reduced in patients affected by schizophrenia ( Fazio et al, 2015 ) fueled interest in examining the role of XA in physiology and pathology. To our knowledge, the cardiovascular effects of XA have never been investigated with the exception of an old study showing that XA and other kynurenine metabolites cause bradycardia in isolated frog hearts ( Rudzit et al, 1986 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Introductionmentioning

confidence: 99%