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INVITED REVIEW

Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation

¹Vascular Medicine Branch, National Heart Lung and Blood Institute, and ²Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; ³Pediatric Anesthesia and Critical Care Medicine Division, Johns Hopkins Hospital, Baltimore, Maryland; ⁴Medical College of Wisconsin, Milwaukee, Wisconsin; ⁵Department of Physics, Wake Forest University, Winston-Salem, North Carolina; and ⁶Department of Pathology and Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama

Accumulating evidence suggests that the simple and ubiquitous anion salt, nitrite (NO₂^–), is a physiological signaling molecule with potential roles in intravascular endocrine nitric oxide (NO) transport, hypoxic vasodilation, signaling, and cytoprotection after ischemia-reperfusion. Human and animal studies of nitrite treatment and NO gas inhalation provide evidence that nitrite mediates many of the systemic therapeutic effects of NO gas inhalation, including peripheral vasodilation and prevention of ischemia-reperfusion-mediated tissue infarction. With regard to nitrite-dependent hypoxic signaling, biochemical and physiological studies suggest that hemoglobin possesses an allosterically regulated nitrite reductase activity that reduces nitrite to NO along the physiological oxygen gradient, potentially contributing to hypoxic vasodilation. An expanded consideration of nitrite as a hypoxia-dependent intrinsic signaling molecule has opened up a new field of research and therapeutic opportunities for diseases associated with regional hypoxia and vasoconstriction.

hemoglobin; hypoxia; S-nitrosated albumin; cysteine 93

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