Published Online
on September 24, 2007

A more recent version of this article appeared on October 16, 2007

This Article Full Text (PDF) All Versions of this Article: 116/16/1821    most recent CIRCULATIONAHA.107.712133v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dejam, A. Articles by Gladwin, M. T. Search for Related Content PubMed PubMed Citation Articles by Dejam, A. Articles by Gladwin, M. T. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ASCORBIC ACID NITRIC OXIDE SODIUM ASCORBATE SODIUM NITRITE Related Collections Endothelium/vascular type/nitric oxide Other Vascular biology Other Research Related Article

Submitted on May 7, 2007
Accepted on August 13, 2007

Nitrite Infusion in Humans and Nonhuman Primates. Endocrine Effects, Pharmacokinetics, and Tolerance Formation

André Dejam MD, PhD, Christian J. Hunter MD, PhD, Carole Tremonti RN, Ryszard M. Pluta MD, Yuen Yi Hon PharmD, George Grimes PharmD, Kristine Partovi MS, Mildred M. Pelletier BS, Edward H. Oldfield MD, Richard O. Cannon III MD, Alan N. Schechter MD, and Mark T. Gladwin MD^*

From the Molecular Medicine Branch (A.D., M.M.P., A.N.S.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md; Vascular Medicine Branch (A.D., C.J.H., C.T., K.P., M.M.P., M.T.G.), and Clinical Cardiology Section (R.O.C.), Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md; Brigham and Women’s Hospital (A.D., C.J.H., C.T.), Harvard Medical School, Boston, Mass; Critical Care Medicine Department (C.J.H., M.T.G.), and Pharmacy Department (Y.Y.H., G.G.), Clinical Center, National Institutes of Health, Bethesda, Md; and Surgical Neurology Branch (R.M.P., E.H.O.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md

^* To whom correspondence should be addressed. E-mail: mgladwin{at}mail.nih.gov.

Background—The recent discovery that nitrite is an intrinsic vasodilator and signaling molecule at near-physiological concentrations has raised the possibility that nitrite contributes to hypoxic vasodilation and to the bioactivity of nitroglycerin and mediates the cardiovascular protective effects of nitrate in the Mediterranean diet. However, important questions of potency, kinetics, mechanism of action, and possible induction of tolerance remain unanswered.

Methods and Results—In the present study, we performed biochemical, physiological, and pharmacological studies using nitrite infusion protocols in 20 normal human volunteers and in nonhuman primates to answer these questions, and we specifically tested 3 proposed mechanisms of bioactivation: reduction to nitric oxide by xanthine oxidoreductase, nonenzymatic disproportionation, and reduction by deoxyhemoglobin. We found that (1) nitrite is a relatively potent and fast vasodilator at near-physiological concentrations; (2) nitrite functions as an endocrine reservoir of nitric oxide, producing remote vasodilation during first-pass perfusion of the opposite limb; (3) nitrite is reduced to nitric oxide by intravascular reactions with hemoglobin and with intravascular reductants (ie, ascorbate); (4) inhibition of xanthine oxidoreductase with oxypurinol does not inhibit nitrite-dependent vasodilation but potentiates it; and (5) nitrite does not induce tolerance as observed with the organic nitrates.

Conclusions—We propose that nitrite functions as a physiological regulator of vascular function and endocrine nitric oxide homeostasis and suggest that it is an active metabolite of the organic nitrates that can be used therapeutically to bypass enzymatic tolerance.

Key words: endothelium-derived factors • free radicals • hemoglobin • nitroglycerin • nitric oxide

Related Article:

Issue Highlights
Circulation 2007 116: 1755. [Full Text]

This article has been cited by other articles:

				D. Kumar, B. G. Branch, C. B. Pattillo, J. Hood, S. Thoma, S. Simpson, S. Illum, N. Arora, J. H. Chidlow Jr., W. Langston, et al. Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis PNAS, May 27, 2008; 105(21): 7540 - 7545. [Abstract] [Full Text] [PDF]

				A. R. Butler and M. Feelisch Therapeutic Uses of Inorganic Nitrite and Nitrate: From the Past to the Future Circulation, April 22, 2008; 117(16): 2151 - 2159. [Abstract] [Full Text] [PDF]

				M. T. Gladwin Evidence Mounts That Nitrite Contributes to Hypoxic Vasodilation in the Human Circulation Circulation, February 5, 2008; 117(5): 594 - 597. [Full Text] [PDF]