Nitrosation of uric acid by peroxynitrite. Formation of a vasoactive nitric oxide donor.
Peroxynitrite (ONOO-), formed by the reaction between nitric oxide (. NO) and superoxide, has been implicated in the etiology of numerous disease processes. Low molecular weight antioxidants, including uric acid, may minimize ONOO---mediated damage to tissues. The tissue-sparing effects of uric acid are typically attributed to oxidant scavenging; however, little attention has been paid to the biology of the reaction products. In this study, a previously unidentified uric acid derivative was detected in ONOO--treated human plasma. The product of the uric acid/ONOO- reaction resulted in endothelium-independent vasorelaxation of rat thoracic aorta, with an EC50 value in the range of 0.03-0.3 microM. Oxyhemoglobin, a .NO scavenger, completely attenuated detectable .NO release and vascular relaxation. Uric acid plus decomposed ONOO- neither released .NO nor altered vascular reactivity. Electrochemical quantification of .NO confirmed that the uric acid/ONOO- reaction resulted in spontaneous (thiol-independent) and protracted (t1/2 approximately 125 min) release of .NO. Mass spectroscopic analysis indicated that the product was a nitrated uric acid derivative. The uric acid nitration/nitrosation product may play a pivotal role in human pathophysiology by releasing .NO, which could decrease vascular tone, increase tissue blood flow, and thereby constitute a role for uric acid not previously described.
Skinner
K A
KA
Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.
White
C R
CR
Patel
R
R
Tan
S
S
Barnes
S
S
Kirk
M
M
Darley-Usmar
V
V
Parks
D A
DA
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D004563:Electrochemistry; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D007700:Kinetics; D013058:Mass Spectrometry; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009566:Nitrates / Q000737:chemistry* / Q000494:pharmacology*; D009569:Nitric Oxide / Q000737:chemistry* / Q000494:pharmacology; D016877:Oxidants / Q000737:chemistry / Q000494:pharmacology; D010108:Oxyhemoglobins / Q000737:chemistry / Q000187:drug effects; D010782:Photolysis; D051381:Rats; D013053:Spectrophotometry; D014527:Uric Acid / Q000097:blood / Q000737:chemistry*; D014664:Vasodilation
C114738:2-nitrito-4-amino-5-hydroxyimidazoline; D007093:Imidazoles; D009566:Nitrates; D016877:Oxidants; D010108:Oxyhemoglobins; C039642:peroxynitric acid; D014527:Uric Acid; D009569:Nitric Oxide