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(Circulation. 2007;116:1821-1831.)
© 2007 American Heart Association, Inc.

Vascular Medicine

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; 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;

Correspondence to Dr Mark T. Gladwin, National Institutes of Health, Bldg 10-CRC, Room 5-5140, 10 Center Dr, Bethesda, MD 20892-1662. E-mail mgladwin{at}mail.nih.gov

Received May 7, 2007; accepted August 13, 2007.

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.

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