Inorganic nitrite therapy: historical perspective and future directions

Abstract

Over the past several years, investigators studying nitric oxide (NO) biology and metabolism have come to learn that the one electron oxidation product of NO, nitrite anion, serves as a unique player in modulating tissue NO bioavailability. Numerous studies have examined how this oxidized metabolite of NO can act as a salvage pathway for maintaining NO equivalents through multiple reduction mechanisms in permissive tissue environments. Moreover, it is now clear that nitrite anion production and distribution throughout the body can act in an endocrine manner to augment NO bioavailability that is important for physiological and pathological processes. These discoveries have led to renewed hope and efforts for an effective NO based therapeutic agent through the unique action of sodium nitrite as an NO pro-drug. More recent studies also indicate that sodium nitrate may also increase plasma nitrite levels via the enterosalivary circulatory system resulting in nitrate reduction to nitrite by microorganisms found within the oral cavity. In this review, we discuss the importance of nitrite anion in several disease models along with an appraisal of sodium nitrite therapy in the clinic, potential caveats of such clinical uses, and future possibilities of nitrite based therapies.

Nitrate/L-arginine Therapy and Nitric Oxide Levels in the Stomach and Liver of Rats

“…Close correlation between plasma and tissue nitrite after nitrite administration has been previously reported [24]. Similar to our results, Raat et al [8] have reported a direct correlation between plasma and liver nitrite concentrations; some authors have suggested that high correlation between serum and some tissue NO x indicates non-specific accumulation of NO x in these organs [27] while others suggest that anion transporters aid regulated and tissue-specific transport of nitrite across cell membranes [24,28].…”

“…The changes we observed in stomach and liver NO x contents following nitrate administration were different; it has been reported that differences in nitrite concentrations between tissues may reflect the degree of NOS activity and the oxidation pathways of NO [24]; however, increased NO x content of the stomach following nitrate administration may also be attributed in part to nitrate absorption from the stomach [25].…”

Mechanisms of Human Erythrocytic Bioactivation of Nitrite

“…However, it is now recognized that nitrite plays important roles in various physiological processes, such as blood pressure control, hypoxic vasodilation, and the inhibition of platelet activation, and its use is being explored for various therapeutic applications (2)(3)(4). For example, administration of nitrite by infusion has been shown to increase blood flow, and its physiological administration through dietary nitrate has been shown to decrease blood pressure (5)(6)(7)(8)(9)(10).…”

The Effect of Sodium Nitrite on Induction of Apoptosis in Human Gastric Adenocarcinoma Epithelia (AGS) Cells

“…The use of sodium nitrite (NaNO 2 ) can be dated back as early as 850 B.C., when it was employed in the meat curing process [1]. It was also used to impart flavor and color to preserved meat [2], and thus had been widely used as a food additive [3].…”

“…In the early 20th century, it was suggested that nitrite might increase the incidence of cancer, and the toxic nature of high nitrite levels had since been confirmed [4] [5]. However, nitrites are also used in the medicinal field [6] and sodium nitrite may have therapeutic potential as a nitric oxide (NO) prodrug in the treatment of tumors, allowing a transient increase in the delivery and efficacy of anti-cancer drugs [1]. To better understand the mechanism under which nitrite-mediated therapy affects tumor progression and development, direct investigation of the effect of sodium nitrite on carcinogenesis, both in vitro and in vivo, is paramount.…”