Abstract
Nitrite-hemoglobin reactions have been studied extensively in vitro, but there is a lack of information on the kinetics of nitrite and its metabolites in humans. In this study, we developed a nine-compartment physiological pharmacokinetic model to describe the in vivo erythrocytic uptake and release and disposition pathways of nitrite, nitrate, methemoglobin, and iron-nitrosyl hemoglobin in the human circulation. Our model revealed that nitrite entered erythrocytes rapidly with a rate constant of 0.256 min−1 (i.e., half-life = 2.71 min). The formation of iron-nitrosyl hemoglobin from nitrite, which involves the reduction of nitrite by deoxyhemoglobin to generate nitric oxide (NO) and reaction of NO with deoxyhemoglobin to form iron-nitrosyl hemoglobin, occurred rapidly as well (k = 2.02 min−1; half-life = 0.343 min = 21 s). The disposition kinetics of methemoglobin was complex. Nitrate formation occurred primarily in erythrocytes through the nitrite-oxyhemoglobin reaction and was higher when nitrite was administered intra-arterially than intravenously. Nitrate reduction was an insignificant metabolic pathway. This study is the first to comprehensively evaluate the kinetics of nitrite and its metabolites in humans and provides unique insights into the rapid equilibrium of nitrite into erythrocytes and conversion to NO in the red cell, which is kinetically associated with vasodilation.
Footnotes
This work was supported by the Intramural Research Program of the National Institutes of Health Clinical Center and National Heart, Lung, and Blood Institute.
M.T.G. is listed as a coinvestor on a National Institutes of Health government patent application on the use of nitrite salts for cardiovascular conditions. All other authors have no conflict of interest.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.034355.
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ABBREVIATIONS:
- NO
- nitric oxide
- eNOS
- endothelial nitric-oxide synthase
- RBC
- red blood cell
- NO2−
- nitrite
- NO3−
- nitrate
- HbFe3+
- methemoglobin
- HbFe2+-NO
- iron-nitrosyl hemoglobin
- HbFe2+
- deoxyhemoglobin
- HbFeO2
- oxyhemoglobin
- N2O3
- dinitrogen trioxide.
- Received May 7, 2010.
- Accepted July 15, 2010.
- U.S. Government work not protected by U.S. copyright
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