Nitrite Infusion in Humans and Nonhuman Primates

Abstract

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.

Different Disappearance Rates of Plasma Nitrite (NO2-) Contribute to Apparent Steady-State Arterio-Venous Differences in Anesthetized Animals

“…However, the sampling procedure employed here is most practical when the circulation time of 4.8-7.5 s in rabbits 35,36) is taken into consideration. Since we have no practical method to elucidate the events that occur within this short period, the kinetic parameters estimated from the present experiments more closely approximate the true physiological values than previous reports, [8][9][10] but nonetheless still lack accuracy.…”

“…However, only limited kinetic data [8][9][10] are presently available, and many problems of NO 2 Ϫ biology await resolution.…”

Conjugated Linoleic Acid Is a Preferential Substrate for Fatty Acid Nitration

“…15 N]O 2 (28). At various times, tissues and plasma were harvested and lipids extracted as described previously using [ 13 C 18 ]NO 2 -LA as an internal standard and analyzed by HPLC-MS/MS.…”

Pharmacology and therapeutic role of inorganic nitrite and nitrate in vasodilatation

“…A lower dose of sodium nitrite, resulting in a plasma concentration of just 350 nmol/l, was found to cause a significant drop in BP in healthy volunteers. In addition, the authors showed a dose-dependent increase in sodium nitrite infusion (0 to 110 μg/kg/min) increased FBF from 2.8 to 12.3 ml/min/100 ml tissue (Dejam et al, 2007).…”

“…It has been shown by a number of research groups that nitrite-derived bioactivity is cardioprotective by minimising cell death by apoptosis (Webb et al, 2004;Duranski et al, 2005;Dezfulian et al, 2007;Shiva et al, 2007aShiva et al, , 2007bTripatara et al, 2007), exerts anti-aggregatory effects (Srihirun et al, 2012;Corti et al, 2013;Park et al, 2013;Velmurugan et al, 2013), inhibits hypoxic and inflammatory pulmonary arterial hypertension (Baliga et al, 2012;Sparacino-Watkins et al, 2012;Bueno et al, 2013), and that it increases forearm blood flow (FBF) and decreases BP by acting as a vasodilator (Cosby et al, 2003;Dejam et al, 2007;Maher et al, 2008). In addition, nitrate has been shown to improve exercise performance by reducing the oxygen cost of exercise in skeletal muscle (Larsen et al, 2011).…”