Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation.
Nitrite anions comprise the largest vascular storage pool of nitric oxide (NO), provided that physiological mechanisms exist to reduce nitrite to NO. We evaluated the vasodilator properties and mechanisms for bioactivation of nitrite in the human forearm. Nitrite infusions of 36 and 0.36 micromol/min into the forearm brachial artery resulted in supra- and near-physiologic intravascular nitrite concentrations, respectively, and increased forearm blood flow before and during exercise, with or without NO synthase inhibition. Nitrite infusions were associated with rapid formation of erythrocyte iron-nitrosylated hemoglobin and, to a lesser extent, S-nitroso-hemoglobin. NO-modified hemoglobin formation was inversely proportional to oxyhemoglobin saturation. Vasodilation of rat aortic rings and formation of both NO gas and NO-modified hemoglobin resulted from the nitrite reductase activity of deoxyhemoglobin and deoxygenated erythrocytes. This finding links tissue hypoxia, hemoglobin allostery and nitrite bioactivation. These results suggest that nitrite represents a major bioavailable pool of NO, and describe a new physiological function for hemoglobin as a nitrite reductase, potentially contributing to hypoxic vasodilation.
Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 7B15 Bethesda, Maryland 20892, USA.
Kenyatta
K
Cosby
Kristine S
KS
Partovi
Jack H
JH
Crawford
Rakesh P
RP
Patel
Christopher D
CD
Reiter
Sabrina
S
Martyr
Benjamin K
BK
Yang
Myron A
MA
Waclawiw
Gloria
G
Zalos
Xiuli
X
Xu
Kris T
KT
Huang
Howard
H
Shields
Daniel B
DB
Kim-Shapiro
Alan N
AN
Schechter
Richard O
RO
Cannon
Mark T
MT
Gladwin
D000328:Adult; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood*; D009572:Nitrite Reductases / Q000097:blood; D009573:Nitrites / Q000097:blood* / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D026403:S-Nitrosothiols / Q000097:blood; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D006454:Hemoglobins; D009573:Nitrites; D026403:S-Nitrosothiols; D009569:Nitric Oxide; C100003:deoxyhemoglobin; D009572:Nitrite Reductases