Matching oxygen delivery with need is of fundamental physiological importance, especially during the perinatal period when oxygen supply to the fetus is often compromised. Nitric oxide (NO) is a key endogenous defense against hypoxia/ischemia by 1) vasodilating arteries to increase oxygen delivery and 2) decreasing oxygen consumption at the level of the mitochondria and hence temporarily reducing oxygen need. Compelling recent evidence indicates that nitrite, NO2-, a ubiquitous anion in the blood of mammals, can be converted to NO by reaction with deoxyhemoglobin. Many experiments suggest that this reaction constitutes a significant source of NO during hypoxia/ischemia. Because the fetus has lower oxygen reserves and is more subject to interrupted oxygen supply than the adult, it would seem logical for protective mechanisms against hypoxia/ischemia to be more pronounced during perinatal life. The production of NO from the reaction between nitrite and deoxyhemoglobin is favored by increased concentrations of nitrite, hemoglobin and H+, all of which are elevated in the blood of hypoxic fetuses more than the adult. The rate of nitrite reduction to NO is also affected by hemoglobin conformation, being maximal when hemoglobin is 40 to 60% oxygen saturated, a range that occurs normally in the fetus but only during hypoxia in the adult. This also suggests the rate of NO production from nitrite and deoxyhemoglobin may be elevated in the fetus compared to the adult. This project will address the general hypothesis that the nitrite/deoxyhemoglobin pathway is a more prevalent source of NO in the fetus than in the adult. Four aspects of the hypothesis will be tested by four specific aims. The first will use chronically instrumented near-term fetal sheep to determine the effects of circulating nitrite on the fetal cardiovasculature and oxygen consumption, and whether these effects are potentiated by hypoxia. The second will examine whether fetal iron-nitrosyl hemoglobin, a byproduct of nitrite metabolism in deoxygenated blood, releases NO more rapidly in vivo than that of adult blood, and hence is a more ready source of NO. In the third aim, in vitro studies are proposed which will determine whether fetal blood is more effective than adult blood at producing vasoactive quantities of NO from nitrite. Finally, we will investigate the physiological importance of a recently discovered reaction between nitrite, NO, and methemoglobin, which may explain how the erythrocyte is capable of releasing vasoactive amounts of NO. The results of these studies will provide a novel and thorough assessment of the reaction of nitrite with deoxyhemoglobin as a source of NO during fetal responses to hypoxia/ischemia. Furthermore, they will provide insight into the therapeutic potential of nitrite as a tool in the treatment of hypoxic/ischemic stress.

Public Health Relevance

Project Narrative Nitrite, upon conversion to nitric oxide (NO) by reaction with deoxyhemoglobin, has been proposed as a key mediator of protective responses to hypoxia/ischemia. If so, nitrite holds wide- ranging potential as a therapeutic agent for the treatment of diseases and injury involving hypoxic/ischemic stress.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
Program Officer
Kaltman, Jonathan R
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Loma Linda University
Schools of Medicine
Loma Linda
United States
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Truong, Giang T; Schröder, Hobe J; Liu, Taiming et al. (2014) Role of nitrite in regulation of fetal cephalic circulation in sheep. J Physiol 592:1785-94
Barrett, Robert D; Bennet, Laura; Blood, Arlin B et al. (2014) Asphyxia and therapeutic hypothermia modulate plasma nitrite concentrations and carotid vascular resistance in preterm fetal sheep. Reprod Sci 21:1483-91
Liu, Taiming; Schroeder, Hobe J; Barcelo, Lisa et al. (2014) Role of blood and vascular smooth muscle in the vasoactivity of nitrite. Am J Physiol Heart Circ Physiol 307:H976-86
Drury, Paul P; Davidson, Joanne O; Mathai, Sam et al. (2014) nNOS inhibition during profound asphyxia reduces seizure burden and improves survival of striatal phenotypic neurons in preterm fetal sheep. Neuropharmacology 83:62-70
Drury, Paul P; Davidson, Joanne O; van den Heuij, Lotte G et al. (2013) Partial neuroprotection by nNOS inhibition during profound asphyxia in preterm fetal sheep. Exp Neurol 250:282-92
Applegate 2nd, Richard L; Ramsingh, Davinder S; Dorotta, Ihab et al. (2013) Evaluation of multiple modes of oximetry monitoring as an index of splanchnic blood flow in a newborn lamb model of hypoxic, ischemic, and hemorrhagic stress. Shock 39:501-6
Papamatheakis, Demosthenes G; Blood, Arlin B; Kim, Joon H et al. (2013) Antenatal hypoxia and pulmonary vascular function and remodeling. Curr Vasc Pharmacol 11:616-40
Blood, Arlin B; Terry, Michael H; Merritt, Travis A et al. (2013) Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambs. Am J Physiol Regul Integr Comp Physiol 304:R136-46
Ibrahim, Yomna I; Ninnis, Janet R; Hopper, Andrew O et al. (2012) Inhaled nitric oxide therapy increases blood nitrite, nitrate, and s-nitrosohemoglobin concentrations in infants with pulmonary hypertension. J Pediatr 160:245-51
Papamatheakis, Demosthenes G; Vemulakonda, Srilakshmi; Blood, Quintin et al. (2011) Preservation of serotonin-mediated contractility in adult sheep pulmonary arteries following long-term high-altitude hypoxia. High Alt Med Biol 12:253-64

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