title: Kynurenine is an endothelium-derived relaxing factor produced during inflammation.
abstract: Control of blood vessel tone is central to vascular homeostasis. Here we show that metabolism of tryptophan to kynurenine by indoleamine 2,3-dioxygenase (Ido) expressed in endothelial cells contributes to arterial vessel relaxation and the control of blood pressure. Infection of mice with malarial parasites (Plasmodium berghei) or induction of endotoxemia in mice led to endothelial expression of Ido, decreased plasma tryptophan concentration, increased kynurenine concentration and hypotension. Pharmacological inhibition of Ido increased blood pressure in systemically inflamed mice but not in mice deficient in Ido or interferon-gamma, which is required for Ido induction. Both tryptophan and kynurenine dilated preconstricted porcine coronary arteries; the dilating effect of tryptophan required the presence of active Ido and an intact endothelium, whereas the effect of kynurenine was endothelium independent. The arterial relaxation induced by kynurenine was mediated by activation of the adenylate and soluble guanylate cyclase pathways. Kynurenine administration decreased blood pressure in a dose-dependent manner in spontaneously hypertensive rats. Our results identify tryptophan metabolism by Ido as a new pathway contributing to the regulation of vascular tone.
authors.affiliation: Centre for Vascular Research, School of Medical Sciences (Pathology) and Bosch Institute, Faculty of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Yutang
authors.initials: Y
authors.lastname: Wang
authors.forename: Hanzhong
authors.initials: H
authors.lastname: Liu
authors.forename: Gavin
authors.initials: G
authors.lastname: McKenzie
authors.forename: Paul K
authors.initials: PK
authors.lastname: Witting
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Michael
authors.initials: M
authors.lastname: Hahn
authors.forename: Dechaboon
authors.initials: D
authors.lastname: Changsirivathanathamrong
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Wu
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Ball
authors.forename: Shane R
authors.initials: SR
authors.lastname: Thomas
authors.forename: Vimal
authors.initials: V
authors.lastname: Kapoor
authors.forename: David S
authors.initials: DS
authors.lastname: Celermajer
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
authors.forename: John F
authors.initials: JF
authors.lastname: Keaney
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Hunt
authors.forename: Roland
authors.initials: R
authors.lastname: Stocker
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000201:enzymology / Q000502:physiology / Q000503:physiopathology; D045462:Endothelium-Dependent Relaxing Factors / Q000502:physiology*; D019446:Endotoxemia / Q000503:physiopathology; D004789:Enzyme Activation / Q000502:physiology; D006162:Guanylate Cyclase / Q000378:metabolism / Q000502:physiology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D007249:Inflammation / Q000503:physiopathology*; D007371:Interferon-gamma / Q000502:physiology; D007737:Kynurenine / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D008288:Malaria / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010962:Plasmodium berghei; D051381:Rats; D011918:Rats, Inbred SHR; D014364:Tryptophan / Q000097:blood / Q000494:pharmacology / Q000502:physiology
chemical_list: D045462:Endothelium-Dependent Relaxing Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D000262:Adenylyl Cyclases; D006162:Guanylate Cyclase