Nitrite enhances RBC hypoxic ATP synthesis and the release of ATP into the vasculature: A new mechanism for nitrite-induced vasodilation

Zeling Cao, Jeffrey B. Bell, Joy G. Mohanty, Enika Nagababu, Joseph M. Rifkind

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


A role for nitric oxide (NO) produced during the reduction of nitrite by deoxygenated red blood cells (RBCs) in regulating vascular dilation has been proposed. It has not, however, been satisfactorily explained how this NO is released from the RBC without first reacting with the large pools of oxyhemoglobin and deoxyhemoglobin in the cell. In this study, we have delineated a mechanism for nitrite-induced RBC vasodilation that does not require that NO be released from the cell. Instead, we show that nitrite enhances the ATP release from RBCs, which is known to produce vasodilation by several different methods including the interaction with purinergic receptors on the endothelium that stimulate the synthesis of NO by endothelial NO synthase. This mechanism was established in vivo by measuring the decrease in blood pressure when injecting nitrite-reacted RBCs into rats. The observed decrease in blood pressure was not observed if endothelial NO synthase was inhibited by N ω-nitro-L-arginine methyl ester (L-NAME) or when any released ATP was degraded by apyrase. The nitrite-enhanced ATP release was shown to involve an increased binding of nitrite-modified hemoglobin to the RBC membrane that displaces glycolytic enzymes from the membrane, resulting in the formation of a pool of ATP that is released from the RBC. These results thus provide a new mechanism to explain nitrite-induced vasodilation.

Original languageEnglish (US)
Pages (from-to)H1494-H1503
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number4
StatePublished - Oct 2009
Externally publishedYes


  • Adenosine 5′-triphosphate
  • Anerobic glycolysis
  • Hypoxia
  • Nitric oxide
  • Nitrite reduction
  • Red blood cell

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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