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

• Published in: Nature reviews. Drug discovery Vol. 7; no. 2; pp. 156 - 167
• Main Authors: Lundberg, Jon O, Weitzberg, Eddie, Gladwin, Mark T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2008; Nature Publishing Group
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer Research; Diet; Drug Design; Humans; Medicin och hälsovetenskap; Medicinal Chemistry; Molecular Medicine; Nitrates - metabolism; Nitrates - pharmacology; Nitrates - therapeutic use; Nitric Oxide - biosynthesis; Nitric Oxide - metabolism; Nitric Oxide - physiology; Nitric Oxide Synthase - metabolism; Nitrites - metabolism; Nitrites - pharmacology; Nitrites - therapeutic use; Pharmacology/Toxicology; review-article; Vasodilation - drug effects
• ISSN: 1474-1776; 1474-1784; 1474-1784; 1474-1776
• DOI: 10.1038/nrd2466

Key Points The inorganic anions nitrite (NO 2 − ) and nitrate (NO 3 − ) are usually viewed as inert end products of nitric oxide (NO) metabolism or unwanted residues in the food chain. Recent studies show that nitrate and nitrite are physiologically recycled in blood and tissue to form NO and other bioactive nitrogen oxides. Thus, they should be viewed as storage pools for NO-like bioactivity, thereby complementing the NO synthase-dependent pathway. There are two major sources of nitrate and nitrite: the endogenous l -arginine/NO-synthase pathway and the diet. Vegetables are particularly rich in nitrate. The bioactivation of nitrate from dietary or endogenous sources requires its initial reduction to nitrite, and this conversion is mainly carried out by commensal bacteria inhabiting the gastrointestinal tract. There are numerous pathways in the body for the further reduction of nitrite to bioactive NO, involving haemoglobin, myoglobin, xanthine oxidoreductase, ascorbate, polyphenols and protons. The generation of NO by all these pathways is greatly enhanced during hypoxia and acidosis, thereby ensuring NO production in situations for which the oxygen-dependent NO-synthase enzyme activities are compromised. Nitrite reduction to NO during physiological and pathological hypoxia appear to contribute to physiological hypoxic signalling, vasodilation, modulation of cellular respiration and the cellular response to ischaemic stress. An expanding number of studies suggest a therapeutic potential for nitrate and nitrite in diseases such as myocardial infarction, stroke, systemic and pulmonary hypertension, and gastric ulceration. The supposedly inert end products of endogenous nitric oxide (NO) metabolism — nitrate and nitrite — have recently been shown to be an important alternative source of NO, complementing the classical NO-synthase pathway. Lundberg and colleagues discuss the emerging role of the nitrate–nitrite–NO pathway, highlighting the therapeutic potential of nitrate and nitrite in various disorders, including myocardial infarction, stroke, systemic and pulmonary hypertension, and gastric ulceration. The inorganic anions nitrate (NO 3 − ) and nitrite (NO 2 − ) 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.