Is There Another Role for Nitric Oxide?

Dietary Nitrates Generate Potentially Mutagenic Concentrations of Nitric Oxide at the Gastroesophageal Junction Iijima K, Moriya A, Wirz A, Kelman W, McColl KEL. Gastroenterology 2002;122:1248–1257. Summary: For the past two decades, dietary nitrates have been implicated in the formation of carcinogenic nitrosamines in humans (Cancer Lett 1995;93:17–48). The evidence relating nitrate exposure to cancer, especially gastric cancer, has been largely based on geographic correlation studies. Shortly after World War II, western countries increased their use of nitrate-based fertilizers and observed a sharp increase in the frequency of gastroesophageal junction (GEJ) adenocarcinoma (Nature 1985;313:620–5). Although the methodology of these earlier studies is being questioned (Br J Nutr 1999;81:349–58), one in vitro study (Scand J Gastroenterol 2002;37:253–61) and one in vivo study (Gastroenterology 2002;122:1248–57) bring a new perspective to this subject. Nitric oxide (NO), an endogenous molecule with many physiologic and potentially detrimental functions, is formed at the GEJ after exposure to dietary nitrates. The most recent article (Gastroenterology 2002;122:1248–57) is summarized here. How is NO formed from dietary nitrates? Green, leafy vegetables are the main source of nitrates in the diet. Twenty-five percent of dietary nitrates absorbed from the intestines are taken up by the salivary glands and resecreted into the mouth. Oral bacteria reduce 30% of the salivary nitrate to nitrite (Food Cosmetics Toxicol 1976;14:549–52). When salivary nitrite interacts with gastric acid in the presence of ascorbic acid, a large amount of NO is formed. In the current article, Iijima et al. (Gastroenterology 2002;122:1248–57) found that NO formation from dietary nitrates is maximal at the GEJ, the location at which swallowed salivary nitrate and gastric acid first meet. This is also the area where dietary nitrate-induced cancers are most common. To explore the regional variations in NO concentrations and pH, Iijima et al. designed an apparatus with two real-time NO sensors and a four-channel pH-recording probe, placed orogastrically. Serum and salivary nitrite concentrations were also monitored. Measurements were taken before and after ingestion of 2 mmol potassium nitrate, the amount of nitrate found in a regular salad portion. Serum and salivary nitrites both increased after potassium nitrate, thus indicating increased NO formation. NO was formed in the gastroesophageal mucosa as detected by the NO sensor, and the amount was higher at the GEJ, identified by the change in the pH. The investigators postulated that the large concentrations of NO formed at the GEJ could nitrosylate sulphydryl groups, deaminate DNA, impair DNA repair enzymes, and thereby promote carcinogenesis. Comment: What is NO and why do we need to know about this interesting molecule? NO was notorious as a major air pollutant and received very little attention before the 1990s (Science 1971;173:45–7). Within the last decade, NO was identified as a messenger molecule responsible for important signal transduction processes in gastrointestinal, cardiovascular, renal, immunologic, central and peripheric nervous and urogenital systems (Science 1992;257:494–6). In physiologic conditions, NO is produced from l-arginine in small quantities by the activation of a constitutive enzyme, NO synthase (nNOS, eNOS). As a gas, NO can diffuse freely across the cell membranes and function as an effective neurotransmitter. In pathologic conditions, such as infection, inflammation, and ischemia, reactive oxygen species are formed, and NO is produced in large quantities from macrophages via the activation of an inducible enzyme, iNOS (J Gastroenterol 1998;33:792–803). Reactive oxygen species could react with NO, which is also a free radical. This would lead to formation of toxic molecules, nitrosative and oxidative stress, depletion of NO, and negation of its beneficial effects. Therefore, depending on its concentration, location, and association with other molecules, NO can have dual effects within the same system. Despite enormous interest in this molecule within the last decade, development of therapeutic agents has been halted because of this double face of NO. In the gastrointestinal system, physiologic concentrations of NO relax the smooth muscle, ensuring the gut peristalsis and the opening of sphincters (Gastroenterology 1992;103:1928–49). NO is involved in esophageal peristaltic contractions and relaxation of the lower esophageal sphincter (Am J Physiol 1991;261:G401–6). Homeostatic concentrations of NO are needed to ensure normal esophageal motility. For example, NO inhibition creates an achalasia type picture in humans (Gastroenterology 1995;109:1241–8). Sildenafil, a phosphodiesterase inhibitor, decreases the lower esophageal sphincter tone in patients with achalasia by augmenting the effects of NO (Gastroenterology 2000;118:253–7). Transient lower esophageal sphincter relaxations, the most common motility abnormality associated with gastroesophageal reflux, may be triggered by NO (Gastroenterology 1998;115:1374–80). Although the effects of supraphysiologic NO concentrations are not well studied in the esophagus, high concentrations of NO have been found in the esophageal mucosa obtained from children with reflux esophagitis (J Pediatr Gastroenterol Nutr 1998:26: 194–9). This article (Gastroenterology 2002;122:1248–57) not only stimulates the debate about the involvement of dietary nitrates in GEJ carcinoma, but also raises an interesting question about the role of dietary factors in the control of gastrointestinal motility. The authors have not performed an esophageal manometry to investigate the effects of high concentrations of NO on lower esophageal sphincter motility; however, NO is a well-known relaxant of the lower esophageal sphincter. More clinical studies will be needed to investigate the role of dietary nitrates in esophageal motility and gastroesophageal reflux. It is possible that in the near future, we will add the green leafy vegetables to the list of dietary factors triggering acid reflux. Especially if the salad is covered with a greasy dressing! Aliye Uc University of Iowa Hospitals and Clinics Iowa, U.S.A.

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