Nitrite as regulator of hypoxic signaling in mammalian physiology

Ernst E. Van Faassen, Soheyl Bahrami, Martin Feelisch, Neil Hogg, Malte Kelm, Daniel B. Kim-Shapiro, Andrey V. Kozlov, Haitao Li, Jon O. Lundberg, Ron Mason, Hans Nohl, Tienush Rassaf, Alexandre Samouilov, Anny Slama-Schwok, Sruti Shiva, Anatoly F. Vanin, Eddie Weitzberg, Jay Zweier, Mark T. Gladwin

Research output: Contribution to journalArticlepeer-review

292 Scopus citations


In this review we consider the effects of endogenous and pharmacological levels of nitrite under conditions of hypoxia. In humans, the nitrite anion has long been considered as metastable intermediate in the oxidation of nitric oxide radicals to the stable metabolite nitrate. This oxidation cascade was thought to be irreversible under physiological conditions. However, a growing body of experimental observations attests that the presence of endogenous nitrite regulates a number of signaling events along the physiological and pathophysiological oxygen gradient. Hypoxic signaling events include vasodilation, modulation of mitochondrial respiration, and cytoprotection following ischemic insult. These phenomena are attributed to the reduction of nitrite anions to nitric oxide if local oxygen levels in tissues decrease. Recent research identified a growing list of enzymatic and non-enzymatic pathways for this endogenous reduction of nitrite. Additional direct signaling events not involving free nitric oxide are proposed. We here discuss the mechanisms and properties of these various pathways and the role played by the local concentration of free oxygen in the affected tissue.

Original languageEnglish (US)
Pages (from-to)683-741
Number of pages59
JournalMedicinal Research Reviews
Issue number5
StatePublished - Sep 2009
Externally publishedYes


  • Hypoxia
  • Ischemia/reperfusion
  • Nitric oxide
  • Nitrite
  • Vasodilation

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Pharmacology


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