The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics

Abstract

The inorganic anions nitrate (NO3-) and nitrite (NO2-) were previously thought to be inert end products of endogenous nitric oxide (NO) metabolism. However, recent studies show that these supposedly inert anions can be recycled in vivo to form NO, representing an important alternative source of NO to the classical L-arginine-NO-synthase pathway, in particular in hypoxic states. This Review discusses the emerging important biological functions of the nitrate-nitrite-NO pathway, and highlights studies that implicate the therapeutic potential of nitrate and nitrite in conditions such as myocardial infarction, stroke, systemic and pulmonary hypertension, and gastric ulceration.

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

“…However, variation in cellular abundance of the microbiome could exist. It is also possible that OVX effects overwhelm the effects of the dietary nitrate‐related gut microbiome, or that nitrate is influencing the gut microbiome in a region of the gut that is not well represented by the stool microbiome, as nitrate is largely absorbed in the upper small intestine 11.…”

“…Since dietary nitrate enhances NO bioavailability in a dose‐dependent fashion 9, this dietary compound may be a viable option for reducing bone loss. Vegetable intake accounts for ∼80% of dietary nitrate consumption in human diets 10; dietary nitrates can be reduced to nitric oxide (NO) via non‐enzymatic reduction by lingual bacteria and a variety of mammalian reductases and increase NO bioavailability through the nitrate‐nitrite‐NO pathway 11, 12. Gastric metabolism of nitrate and nitrite is associated with both health benefits and risks 13, including the formation of potentially carcinogenic nitrosamines promoted by nitrites in processed meats which can be inhibited by flavonoids and other compounds in vegetables 14.…”

Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm

“…This is an alternative mechanism to the classical pathway in which NO is produced by oxidation of L‐arginine in a reaction catalysed by nitric oxide synthase (NOS) (Lundberg et al ., 2008). NO generated through the nitrate–nitrite–NO pathway has been suggested to involve a series of nitric oxide synthase (NOS)‐independent and oxygen‐independent reactions.…”

“…NO generated through the nitrate–nitrite–NO pathway has been suggested to involve a series of nitric oxide synthase (NOS)‐independent and oxygen‐independent reactions. However, the precise mechanism(s) for nitrite conversion to NO remains to be fully elucidated because a number of enzymes have been implicated in the catalysis of nitrite to NO in various tissue compartments (Lundberg et al ., 2008). Green leafy vegetables (such as spinach and beetroot) are the major source of dietary inorganic nitrate.…”

Nitrite Therapy Ameliorates Myocardial Dysfunction via H 2 S and Nuclear Factor‐Erythroid 2‐Related Factor 2 (Nrf2)‐Dependent Signaling in Chronic Heart Failure

“…Nitric oxide (NO) is a gaseous signaling molecule that plays a pivotal role in controlling cardiovascular homeostasis 1, 2. NO is synthesized endogenously via 3 isoforms of NO synthase (NOS) as well as by nonenzymatic reduction of nitrate (${\text{NO}}_3^{-}$) and nitrite (${\text{NO}}_2^{-}$).…”