The reaction between nitrite and hemoglobin: the role of nitrite in hemoglobin-mediated hypoxic vasodilation

doi:10.1016/j.jinorgbio.2004.10.034

Journal of Inorganic Biochemistry

Volume 99, Issue 1, January 2005, Pages 237-246

https://doi.org/10.1016/j.jinorgbio.2004.10.034 Get rights and content

Abstract

The reaction between nitrite and hemoglobin has been studied for over a century. However, recent evidence indicating nitrite is a latent vasodilatory agent that can be activated by its reaction with deoxyhemoglobin has led to renewed interest in this reaction. In this review we survey, in the context of our own recent studies, the chemical reactivity of nitrite with oxyhemoglobin, deoxyhemoglobin and methemoglobin, and place these reactions in both a physiological and pharmacological/therapeutic context.

Introduction

Recent evidence suggests that plasma nitrite anion represents a latent substance that can be activated by hemoglobin in areas of hypoxia to elicit vasodilation [1]. The mechanisms by which activation and vasodilation occur are currently uncertain and are under intense study. Although the reaction between nitrite and hemoglobin has been appreciated since at least the middle 1800s, a definitive mechanistic understanding of these reactions is lacking. In this review, we survey published mechanisms in the context of our own recent studies, and highlight how such mechanisms either complement or are at odds with the recent physiological findings. In addition we place the nitrite/hemoglobin reaction in its physiological and pharmacological context.

Section snippets

The reaction between nitrite and oxyhemoglobin

Ask most researchers in the nitric oxide or hemoglobin fields “what happens when you mix nitrite with oxyHb” and they will say the same thing: nitrite gets oxidized to nitrate and the hemoglobin gets oxidized to the ferric form (methemoglobin or metHb). Ask these same researchers for the mechanism and you will likely also get the same answer: “It’s complicated!” Nevertheless there is often an underlying assumption that this reaction must be responsible for the oxidation of nitrite to nitrate in

Role of the nitrite–deoxyhemoglobin reaction in vasodilation

As outlined above, understanding the interactions of Hb and NO or nitrite poses an intriguing problem to biochemists, biophysicists, vascular biologists, physiologists and hematologists alike. The emergence of the concept that these reactions are playing roles in as fundamental a process as blood flow underscores the importance of understanding reaction mechanisms. We now shift the focus of this article to discuss our current understanding of how Hb and RBCs modulates blood flow through

Summary and conclusions

Fig. 2 summarizes the essential features of the nitrite/hemoglobin hypothesis. The interaction of nitrite with deoxyHb and not oxyHb generates a diffusible vasodilator with the properties of nitric oxide. The barrier to diffusion that exists at the red cell membrane will limit the ability of red cells to destroy NO generated in the extracellular space and allow diffusion of red-cell generated NO to the smooth muscle tissue. The major fundamental differences of the nitrite/hemoglobin hypothesis

Acknowledgements

This work was supported by NIH grants HL58091 (DK-S), GM55792 (NH) and HL70146 (RPP). We would also like to thank Dr. Celia Bonaventura for helpful discussions.

References (44)

W. Marshall et al.
J. Biol. Chem.
(1945)
H. Kosaka et al.
Biochim. Biophys. Acta
(1979)
M.P. Doyle et al.
J. Biol. Chem.
(1981)
W.J. Wallace et al.
Biochem. Biophys. Res. Commun.
(1975)
C.H. Taboy et al.
J. Biol. Chem.
(2000)
M.P. Doyle et al.
Biochem. Biophys. Res. Commun.
(1982)
E. Lissi
Free Radic. Biol. Med.
(1998)
R.E. Brantley et al.
J. Biol. Chem.
(1993)
N.Y. Spencer et al.
J. Biol. Chem.
(2000)
M.P. Doyle et al.
J. Biol. Chem.
(1981)

D.B. Kim-Shapiro

Free Radic. Biol. Med.

(2004)

E. Nagababu et al.

J. Biol. Chem.

(2003)

C.E. Cooper

Biochim. Biophys. Acta

(1999)

L.L. Bondoc et al.

J. Biol. Chem.

(1989)

X. Liu et al.

J. Biol. Chem.

(1998)

P. Kleinbongard et al.

Free Radic. Biol. Med.

(2003)

F.B. Jensen

Comp. Biochem. Physiol. A

(2003)

C. Bonaventura et al.

J. Biol. Chem.

(2002)

M.T. Gladwin et al.

J. Biol. Chem.

(2002)

K. Cosby et al.

Nat. Med.

(2003)

A. Gamgee

Philos. Trans. R. Soc. London

(1868)

J. Haldane et al.

J. Physiol.

(1897)

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The reaction between nitrite and hemoglobin: the role of nitrite in hemoglobin-mediated hypoxic vasodilation

Abstract

Introduction

Section snippets

The reaction between nitrite and oxyhemoglobin

Role of the nitrite–deoxyhemoglobin reaction in vasodilation

Summary and conclusions

Acknowledgements

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Free Radic. Biol. Med.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Free Radic. Biol. Med.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

Free Radic. Biol. Med.

Comp. Biochem. Physiol. A

J. Biol. Chem.

J. Biol. Chem.

Nat. Med.

Philos. Trans. R. Soc. London

J. Physiol.