Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation.
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.


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.
Dejam
André
A
Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Hunter
Christian J
CJ
Tremonti
Carole
C
Pluta
Ryszard M
RM
Hon
Yuen Yi
YY
Grimes
George
G
Partovi
Kristine
K
Pelletier
Mildred M
MM
Oldfield
Edward H
EH
Cannon
Richard O
RO
Schechter
Alan N
AN
Gladwin
Mark T
MT
D000328:Adult; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D001205:Ascorbic Acid / Q000008:administration & dosage; D004361:Drug Tolerance; D004703:Endocrine System / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007261:Infusions, Intra-Arterial; D008252:Macaca fascicularis; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D010117:Oxypurinol / Q000008:administration & dosage; D012039:Regional Blood Flow / Q000187:drug effects; D012977:Sodium Nitrite / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014969:Xanthine Oxidase / Q000378:metabolism
D000975:Antioxidants; D004791:Enzyme Inhibitors; D006454:Hemoglobins; D014665:Vasodilator Agents; D009569:Nitric Oxide; C100003:deoxyhemoglobin; D014969:Xanthine Oxidase; D010117:Oxypurinol; D012977:Sodium Nitrite; D001205:Ascorbic Acid