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PMID: 16195332 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation.

Blood ·Vol. 107 ·No. 2 ·2006-01-15 ·Pages 566-74

Crawford JH, Isbell TS, Huang Z, Shiva S, Chacko BK, Schechter AN, Darley-Usmar VM, Kerby JD, Lang JD, Kraus D, Ho C, Gladwin MT, Patel RP

Abstract

Local vasodilation in response to hypoxia is a fundamental physiologic response ensuring oxygen delivery to tissues under metabolic stress. Recent studies identify a role for the red blood cell (RBC), with hemoglobin the hypoxic sensor. Herein, we investigate the mechanisms regulating this process and explore the relative roles of adenosine triphosphate, S-nitrosohemoglobin, and nitrite as effectors. We provide evidence that hypoxic RBCs mediate vasodilation by reducing nitrite to nitric oxide (NO) and ATP release. NO dependence for nitrite-mediated vasodilation was evidenced by NO gas formation, stimulation of cGMP production, and inhibition of mitochondrial respiration in a process sensitive to the NO scavenger C-PTIO. The nitrite reductase activity of hemoglobin is modulated by heme deoxygenation and heme redox potential, with maximal activity observed at 50% hemoglobin oxygenation (P(50)). Concomitantly, vasodilation is initiated at the P(50), suggesting that oxygen sensing by hemoglobin is mechanistically linked to nitrite reduction and stimulation of vasodilation. Mutation of the conserved beta93cys residue decreases the heme redox potential (ie, decreases E(1/2)), an effect that increases nitrite reductase activity and vasodilation at any given hemoglobin saturation. These data support a function for RBC hemoglobin as an allosterically and redox-regulated nitrite reductase whose "enzyme activity" couples hypoxia to increased NO-dependent blood flow.

MeSH Terms
Adenosine Triphosphate/metabolism Allosteric Regulation Cell Hypoxia Cyclic GMP/metabolism Erythrocytes/metabolism Heme/chemistry Hemoglobins/metabolism,pharmacology Humans Mitochondria/metabolism Mutation Nitric Oxide/metabolism Nitrite Reductases/metabolism Nitrites/pharmacology Oxidation-Reduction Oxygen/metabolism Respiration Vasodilation
Chemicals
Hemoglobins Nitrites S-nitrosohemoglobin Nitric Oxide Heme Adenosine Triphosphate Nitrite Reductases Cyclic GMP Oxygen
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Crawford Jack H
Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, 35294, USA.
Isbell T Scott
Huang Zhi
Shiva Sruti
Chacko Balu K
Schechter Alan N
Darley-Usmar Victor M
Kerby Jeffrey D
Lang John D
Kraus David
Ho Chien
Gladwin Mark T
Patel Rakesh P
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2005-07-2668
Published
2006-01-15
Epub
2005-00-29
Pages
566-74
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC1895612
Subset
IM
Grants
NHLBI NIH HHS · HL-24525 · United States
NHLBI NIH HHS · HL70146 · United States
NIGMS NIH HHS · T32 GM08361 · United States
Intramural NIH HHS · United States
External Links
PubMed source DOI: 10.1182/blood-2005-07-2668 PMC Full Text View journal details
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