The reversible redox conversion of nitrite and nitric oxide ((•)NO) in a physiological setting is now widely accepted. Nitrite has long been identified as a stable intermediate of (•)NO oxidation but several lines of evidence support the reduction of nitrite to nitric oxide in vivo. In the gut, this notion implies that nitrate from dietary sources fuels the longstanding production of nitrite in the oral cavity followed by univalent reduction to (•)NO in the stomach. Once formed, (•)NO boosts a network of reactions, including the production of higher nitrogen oxides that may have a physiological impact via the post-translational modification of proteins and lipids. Dietary compounds, such as polyphenols, and different prandial states (secreting specific gastric mediators) modulate the outcome of these reactions. The gut has unusual characteristics that modulate nitrite and (•)NO redox interplay: (1) wide range of pH (neutral vs acidic) and oxygen tension (c.a. 70 Torr in the stomach and nearly anoxic in the colon), (2) variable lumen content and (3) highly developed enteric nervous system (sensitive to (•)NO and dietary compounds, such as glutamate). The redox interplay of nitrite and (•)NO might also participate in the regulation of brain homeostasis upon neuronal glutamatergic stimulation in a process facilitated by ascorbate and a localized and transient decrease of oxygen tension. In a way reminiscent of that occurring in the stomach, a nitrite/(•)NO/ascorbate redox interplay in the brain at glutamatergic synapses, contributing to local (•)NO increase, may impact on (•)NO-mediated process. We here discuss the implications of the redox conversion of nitrite to (•)NO in the gut, how nitrite-derived (•)NO may signal from the digestive to the central nervous system, influencing brain function, as well as a putative ascorbate-driven nitrite/NO pathway occurring in the brain.

Until recently, nitrite has been considered a stable and inert metabolite of nitric oxide ( • NO) metabolism. This view is now changing as it has been shown that nitrite can be reduced back to • NO and thus one may consider a reversible interaction regarding ˙NO:nitrite couple. Not only physiological regulatory actions have been assigned to nitrite but also may represent, in addition to nitrate, the largest ˙NO reservoir in the body. This notion has obvious importance when considering that ˙NO is a ubiquitous regulator of cell functions, ranging from neuromodulation to the regulation of vascular tone. Particularly in the stomach, following ingestion of nitrate and food or beverages-containing polyphenols, a rich chemistry occurs in which ˙NO, ˙NO-derived species and nitroso or nitrated derivatives may be formed. Most of these molecules may play an important role in vivo. For instance, it has been shown that polyphenol-catalyzed nitrite reduction to ˙NO may induce local vasodilation and that ethanol (from wine) reacts with ˙NO-derived species yielding nitroso derivatives endowed with ˙NO-donating properties. Thus, this review reveals new pathways for the biological effects of dietary nitrite encompassing its interaction with dietary components (polyphenols, red wine, lipids), yielding products with impact on human physiology and pathology, namely cardiovascular, urinary and gastrointestinal systems. Novel therapeutic strategies are therefore expected to follow the elucidation of the mechanisms of nitrite biology.

Dietary polyphenols are complex, natural compounds with recognized health benefits. Initially attractive to the biomedical area due to their in vitro antioxidant properties, the biological implications of polyphenols are now known to be far from their acute ability to scavenge free radicals but rather to modulate redox signaling pathways. Actually, it is now recognized that dietary polyphenols are extensively metabolized in vivo and that the chemical, biophysical and biological properties of their metabolites are, in most cases, quite different from the ones of the parent molecules. Hence, the study of the metabolic, absorptive and signaling pathways of both phenolics and derivatives has become a major issue. In this paper we propose a short-cut for the systemic effects of polyphenols in connection with nitric oxide (˙NO) biology. This free radical is a ubiquitous signaling molecule with pivotal functions in vivo. It is produced through an enzymatic pathway and also through the reduction of dietary nitrate and nitrite in the human stomach. At acidic gastric pH, dietary polyphenols, in the form they are conveyed in foods and at high concentration, not only promote nitrite reduction to ˙NO but also embark in a complex network of chemical reactions to produce higher nitrogen oxides with signaling functions, namely by inducing post-translational modifications. Modified endogenous molecules, such as nitrated proteins and lipids, acquire important physiological functions. Thus, local and systemic effects of ˙NO such as modulation of vascular tone, mucus production in the gut and protection against ischemia–reperfusion injury are, in this sense, triggered by dietary polyphenols. Evidence to support the signaling and biological effects of polyphenols by modulation of the nitrate–nitrite–NO pathway will be herein provided and discussed. General actions of polyphenols encompassing absorption and metabolism in the intestine/liver are short-cut via the production of diffusible species in the stomach that have not only a local but also a general impact.