Kynurenine is an endothelium-derived relaxing factor produced during inflammation.
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.
Wang
Yutang
Y
Centre for Vascular Research, School of Medical Sciences (Pathology) and Bosch Institute, Faculty of Medicine, University of Sydney, Sydney, Australia.
Liu
Hanzhong
H
McKenzie
Gavin
G
Witting
Paul K
PK
Stasch
Johannes-Peter
JP
Hahn
Michael
M
Changsirivathanathamrong
Dechaboon
D
Wu
Ben J
BJ
Ball
Helen J
HJ
Thomas
Shane R
SR
Kapoor
Vimal
V
Celermajer
David S
DS
Mellor
Andrew L
AL
Keaney
John F
JF
Hunt
Nicholas H
NH
Stocker
Roland
R
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
D045462:Endothelium-Dependent Relaxing Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D000262:Adenylyl Cyclases; D006162:Guanylate Cyclase