Archives of Pharmacal Research

, Volume 32, Issue 8, pp 1119–1126 | Cite as

NO generation from inorganic nitrate and nitrite: Role in physiology, nutrition and therapeutics

  • Jon O. LundbergEmail author
  • Eddie Weitzberg


The nitrate-nitrite-NO pathway is emerging as a likely regulator of physiological functions in the gastrointestinal tract and in the cardiovascular system. In particular, it might serve as a backup system to ensure NO like bioactivity also in situations when the endogenous L-arginine/NO synthase pathway is dysfunctional. In addition, this alternative pathway can be harnessed therapeutically in prevention and treatment of disease. Finally, there is an intriguing nutritional aspect to this, since the major supply of nitrate and nitrite in our bodies comes from our everyday diet. Here we review recent advances in this exciting area of research.

Key words

Nitric oxide Hypoxia Cardiovascular Diet Peroxynitrite Superoxide Bacteria 


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  1. Appel, L. J., Moore, T. J., Obarzanek, E., Vollmer, W. M., Svetkey, L. P., Sacks, F. M., Bray, G. A., Vogt, T. M., Cutler, J. A., Windhauser, M. M., Lin, P. H., and Karanja, N., A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N. Engl. J. Med., 336, 1117–1124 (1997).Google Scholar
  2. Benjamin, N., O’driscoll, F., Dougall, H., Duncan, C., Smith, L., Golden, M., and Mckenzie, H., Stomach NO synthesis. Nature, 368, 502 (1994).PubMedCrossRefGoogle Scholar
  3. Bjorne, H., Weitzberg, E., and Lundberg, J. O., Intragastric generation of antimicrobial nitrogen oxides from saliva-physiological and therapeutic considerations. Free Radic. Biol. Med., 41, 1404–1412 (2006).PubMedCrossRefGoogle Scholar
  4. Bjorne, H. H., Petersson, J., Phillipson, M., Weitzberg, E., Holm, L., and Lundberg, J. O., Nitrite in saliva increases gastric mucosal blood flow and mucus thickness. J. Clin. Invest., 113, 106–114 (2004).Google Scholar
  5. Bryan, N. S., Calvert, J. W., Elrod, J. W., Gundewar, S., Ji, S. Y., and Lefer, D. J., Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury. Proc. Natl. Acad. Sci. USA, 104, 19144–19149 (2007).PubMedCrossRefGoogle Scholar
  6. Bryan, N. S., Fernandez, B. O., Bauer, S. M., Garcia-Saura, M. F., Milsom, A. B., Rassaf, T., Maloney, R. E., Bharti, A., Rodriguez, J., and Feelisch, M., Nitrite is signalling molecule and regulator of gene expression in mammalian tissue. Nat. Chem. Biol., 1, 290–297 (2005).PubMedCrossRefGoogle Scholar
  7. Carlsson, S., Wiklund, N. P., Engstrand, L., Weitzberg, E., and Lundberg, J. O., Effects of pH, nitrite, and ascorbic acid on nonenzymatic nitric oxide generation and bacterial growth in urine. Nitric Oxide, 5, 580–586 (2001).PubMedCrossRefGoogle Scholar
  8. Castello, P. R., David, P. S., Mcclure, T., Crook, Z., and Poyton, R. O., Mitochondrial cytochrome oxidase produces nitric oxide under hypoxic conditions: implications for oxygen sensing and hypoxic signaling in eukaryotes. Cell Metab, 3, 277–287 (2006).PubMedCrossRefGoogle Scholar
  9. Chobanian, A. V., Bakris, G. L., Black, H. R., Cushman, W. C., Green, L. A., Izzo, J. L., Jr., Jones, D. W., Materson, B. J., Oparil, S., Wright, J. T., Jr., and Roccella, E. J., The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA, 289, 2560–2772 (2003).PubMedCrossRefGoogle Scholar
  10. Cosby, K., Partovi, K. S., Crawford, J. H., Patel, R. P., Reiter, C. D., Martyr, S., Yang, B. K., Waclawiw, M. A., Zalos, G., Xu, X., Huang, K. T., Shields, H., Kim-Shapiro, D. B., Schechter, A. N., Cannon, R. O., and Gladwin, M. T., Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med, 9, 1498–505 (2003).PubMedCrossRefGoogle Scholar
  11. Duncan, C., Li, H., Dykhuizen, R., Frazer, R., Johnston, P., Macknight, G., Smith, L., Lamza, K., Mckenzie, H., Batt, L., Kelly, D., Golden, M., Benjamin, N., and Leifert, C., Protection against oral and gastrointestinal diseases: importance of dietary nitrate intake, oral nitrate reduction and enterosalivary nitrate circulation. Comp. Biochem. Physiol. A Physiol., 118, 939–948 (1997).PubMedCrossRefGoogle Scholar
  12. Duranski, M. R., Greer, J. J., Dejam, A., Jaganmohan, S., Hogg, N., Langston, W., Patel, R. P., Yet, S. F., Wang, X., Kevil, C. G., Gladwin, M. T., and Lefer, D. J., Cytoprotective effects of nitrite during in vivo ischemiareperfusion of the heart and liver. J. Clin. Invest., 115, 1232–1240 (2005).PubMedGoogle Scholar
  13. Dykhuizen, R. S., Frazer, R., Duncan, C., Smith, C. C., Golden, M., Benjamin, N., and Leifert, C. Antimicrobial effect of acidified nitrite on gut pathogens: importance of dietary nitrate in host defense. Antimicrob. Agents. Chemother., 40, 1422–1425 (1996).PubMedGoogle Scholar
  14. Furchgott, R. F. and Bhadrakom, S., Reactions of strips of rabbit aorta to epinephrine, isopropylarterenol, sodium nitrite and other drugs. J. Pharmacol. Exp. Ther., 108, 129–143 (1953).PubMedGoogle Scholar
  15. Gago, B., Lundberg, J. O., Barbosa, R. M., and Laranjinha, J., Red wine-dependent reduction of nitrite to nitric oxide in the stomach. Free Radic. Biol. Med., 43, 1233–1242 (2007).PubMedCrossRefGoogle Scholar
  16. Gladwin, M. T., Schechter, A. N., Kim-Shapiro, D. B., Patel, R. P., Hogg, N., Shiva, S., Cannon, R. O., 3rd, Kelm, M., Wink, D. A., Espey, M. G., Oldfield, E. H., Pluta, R. M., Freeman, B. A., Lancaster, J. R., Jr., Feelisch, M., and Lundberg, J. O., The emerging biology of the nitrite anion. Nat. Chem. Biol., 1, 308–314 (2005).PubMedCrossRefGoogle Scholar
  17. Gladwin, M. T., Shelhamer, J. H., Schechter, A. N., Pease-Fye, M. E., Waclawiw, M. A., Panza, J. A., Ognibene, F. P., and Cannon, R. O., 3rd Role of circulating nitrite and S-nitrosohemoglobin in the regulation of regional blood flow in humans. Proc. Natl. Acad. Sci. USA, 97, 11482–11487 (2000).PubMedCrossRefGoogle Scholar
  18. Godber, B. L., Doel, J. J., Sapkota, G. P., Blake, D. R., Stevens, C. R., Eisenthal, R., and Harrison, R., Reduction of nitrite to nitric oxide catalyzed by xanthine oxidoreductase. J. Biol. Chem., 275, 7757–7763 (2000).PubMedCrossRefGoogle Scholar
  19. Govoni, M., Jansson, E. A., Weitzberg, E., and Lundberg, J. O., The increase in plasma nitrite after a dietary nitrate load is markedly attenuated by an antibacterial mouthwash. Nitric Oxide, (2008).Google Scholar
  20. Hendgen-Cotta, U. B., Merx, M. W., Shiva, S., Schmitz, J., Becher, S., Klare, J. P., Steinhoff, H. J., Goedecke, A., Schrader, J., Gladwin, M. T., Kelm, M., and Rassaf, T., Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemiareperfusion injury. Proc. Natl. Acad. Sci. USA, 105, 10256–10261 (2008).PubMedCrossRefGoogle Scholar
  21. Jansson, E. A., Huang, L., Malkey, R., Govoni, M., Nihlen, C., Olsson, A., Stensdotter, M., Petersson, J., Holm, L., Weitzberg, E., and Lundberg, J. O., A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis. Nat. Chem. Biol., (2008).Google Scholar
  22. Jansson, E. A., Petersson, J., Reinders, C., Sobko, T., Bjorne, H., Phillipson, M., Weitzberg, E., Holm, L., and Lundberg, J. O., Protection from nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers by dietary nitrate. Free Radic. Biol. Med., 42, 510–518 (2007).PubMedCrossRefGoogle Scholar
  23. Jung, K. H., Chu, K., Ko, S. Y., Lee, S. T., Sinn, D. I., Park, D. K., Kim, J. M., Song, E. C., Kim, M., and Roh, J. K., Early intravenous infusion of sodium nitrite protects brain against in vivo ischemia-reperfusion injury. Stroke, 37, 2744–2750 (2006).PubMedCrossRefGoogle Scholar
  24. Kozlov, A. V., Dietrich, B., and Nohl, H., Various intracellular compartments cooperate in the release of nitric oxide from glycerol trinitrate in liver. Br. J. Pharmacl., 139, 989–997 (2003).CrossRefGoogle Scholar
  25. Kozlov, A. V., Staniek, K., and Nohl, H., Nitrite reductase activity is a novel function of mammalian mitochondria. FEBS Lett., 454, 127–130 (1999).PubMedCrossRefGoogle Scholar
  26. Kumar, D., Branch, B. G., Pattillo, C. B., Hood, J., Thoma, S., Simpson, S., Illum, S., Arora, N., Chidlow, J. H., Jr., Langston, W., Teng, X., Lefer, D. J., Patel, R. P., and Kevil, C. G., Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis. Proc. Natl. Acad. Sci. USA, 105, 7540–7545 (2008).PubMedCrossRefGoogle Scholar
  27. Lang, J. D., Jr., Teng, X., Chumley, P., Crawford, J. H., Isbell, T. S., Chacko, B. K., Liu, Y., Jhala, N., Crowe, D. R., Smith, A. B., Cross, R. C., Frenette, L., Kelley, E. E., Wilhite, D. W., Hall, C. R., Page, G. P., Fallon, M. B., Bynon, J. S., Eckhoff, D. E., and Patel, R. P., Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation. J. Clin. Invest., 117, 2583–2591 (2007).PubMedCrossRefGoogle Scholar
  28. Larauche, M., Bueno, L., and Fioramonti, J., Effect of dietary nitric oxide on gastric mucosal mast cells in absence or presence of an experimental gastritis in rats. Life Sci., 73, 1505–1516 (2003).PubMedCrossRefGoogle Scholar
  29. Larsen, F. J., Ekblom, B., Sahlin, K., Lundberg, J. O., and Weitzberg, E. Effects of dietary nitrate on blood pressure in healthy volunteers. N. Engl. J. Med., 355, 2792–2793 (2006).PubMedCrossRefGoogle Scholar
  30. Larsen, F. J., Weitzberg, E., Lundberg, J. O., and Ekblom, B., Effects of dietary nitrate on oxygen cost during exercise. Acta Physiol (Oxf)., 191, 59–66 (2007).CrossRefGoogle Scholar
  31. Li, H., Samouilov, A., Liu, X., and Zweier, J. L. Characterization of the magnitude and kinetics of xanthine oxidase-catalyzed nitrite reduction. Evaluation of its role in nitric oxide generation in anoxic tissues. J. Biol. Chem., 276, 24482–24489 (2001).PubMedCrossRefGoogle Scholar
  32. Lundberg, J. O. and Govoni, M., Inorganic nitrate is a possible source for systemic generation of nitric oxide. Free Radic. Biol. Med., 37, 395–400 (2004).PubMedCrossRefGoogle Scholar
  33. Lundberg, J. O. and Weitzberg, E., NO generation from nitrite and its role in vascular control. Arterioscler. Thromb. Vasc. Biol., 25, 915–922 (2005).PubMedCrossRefGoogle Scholar
  34. Lundberg, J. O., Weitzberg, E., Cole, J. A., and Benjamin, N., Nitrate, bacteria and human health. Nat. Rev. Microbiol., 2, 593–602 (2004).PubMedCrossRefGoogle Scholar
  35. Lundberg, J. O., Weitzberg, E., and Gladwin, M. T., The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat. Rev. Drug. Discov., 7, 156–167 (2008).PubMedCrossRefGoogle Scholar
  36. Lundberg, J. O., Weitzberg, E., Lundberg, J. M., and Alving, K., Intragastric nitric oxide production in humans: measurements in expelled air. Gut, 35, 1543–1546 (1994).PubMedCrossRefGoogle Scholar
  37. Mathru, M., Huda, R., Solanki, D. R., Hays, S., and Lang, J. D., Inhaled nitric oxide attenuates reperfusion inflammatory responses in humans. Anesthesiology, 106, 275–282 (2007).PubMedCrossRefGoogle Scholar
  38. Millar, T. M., Stevens, C. R., Benjamin, N., Eisenthal, R., Harrison, R., and Blake, D. R. Xanthine oxidoreductase catalyses the reduction of nitrates and nitrite to nitric oxide under hypoxic conditions. FEBS Lett., 427, 225–228 (1998).PubMedCrossRefGoogle Scholar
  39. Miyoshi, M., Kasahara, E., Park, A. M., Hiramoto, K., Minamiyama, Y., Takemura, S., Sato, E. F., and Inoue, M., Dietary nitrate inhibits stress-induced gastric mucosal injury in the rat. Free Radic. Res., 37, 85–90. (2003).PubMedCrossRefGoogle Scholar
  40. Modin, A., Bjorne, H., Herulf, M., Alving, K., Weitzberg, E., and Lundberg, J. O., Nitrite-derived nitric oxide: A possible mediator of ‘acidic-metabolic’ vasodilation. Acta. Physiol. Scand., 171, 9–16 (2001).PubMedCrossRefGoogle Scholar
  41. Moncada, S. and Higgs, A., The L-arginine-nitric oxide pathway. N. Engl. J. Med., 329, 2002–2012 (1993).PubMedCrossRefGoogle Scholar
  42. Nagababu, E., Ramasamy, S., Abernethy, D. R., and Rifkind, J. M., Active nitric oxide produced in the red cell under hypoxic conditions by deoxyhemoglobin-mediated nitrite reduction. J. Biol. Chem., 278, 46349–46356 (2003).PubMedCrossRefGoogle Scholar
  43. Peri, L., Pietraforte, D., Scorza, G., Napolitano, A., Fogliano, V., and Minetti, M., Apples increase nitric oxide production by human saliva at the acidic pH of the stomach: a new biological function for polyphenols with a catechol group? Free Radic. Biol. Med., 39, 668–81 (2005).PubMedCrossRefGoogle Scholar
  44. Petersson, J., Nitrate, nitrite and nitric oxide in gastric mucosal defense. Uppsala University. Uppsala, Uppsala, (2008).Google Scholar
  45. Petersson, J., Phillipson, M., Jansson, E. A., Patzak, A., Lundberg, J. O., and Holm, L., Dietary nitrate increases gastric mucosal blood flow and mucosal defense. Am. J. Physiol. Gastrointest. Liver. Physiol., 292, G718–G724 (2007).PubMedCrossRefGoogle Scholar
  46. Rassaf, T., Flogel, U., Drexhage, C., Hendgen-Cotta, U., Kelm, M., and Schrader, J., Nitrite reductase function of deoxymyoglobin: oxygen sensor and regulator of cardiac energetics and function. Circ. Res., 100, 1749–1754 (2007).PubMedCrossRefGoogle Scholar
  47. Shiva, S., Huang, Z., Grubina, R., Sun, J., Ringwood, L. A., Macarthur, P. H., Xu, X., Murphy, E., Darley-Usmar, V. M., and Gladwin, M. T., Deoxymyoglobin is a nitrite reductase that generates nitric oxide and regulates mitochondrial respiration. Circ. Res., 100, 654–661 (2007a).PubMedCrossRefGoogle Scholar
  48. Shiva, S., Sack, M. N., Greer, J. J., Duranski, M., Ringwood, L. A., Burwell, L., Wang, X., Macarthur, P. H., Shoja, A., Raghavachari, N., Calvert, J. W., Brookes, P. S., Lefer, D. J., and Gladwin, M. T., Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J. Exp. Med., 204, 2089–2102 (2007b).PubMedCrossRefGoogle Scholar
  49. Sobko, T., Reinders, C., Norin, E., Midtvedt, T., Gustafsson, L. E., and Lundberg, J. O., Gastrointestinal nitric oxide generation in germ-free and conventional rats. Am. J. Physiol. Gastrointest. Liver. Physiol., 287, G993–G997 (2004).PubMedCrossRefGoogle Scholar
  50. Spiegelhalder, B., Eisenbrand, G., and Preussman, R., Influence of dietary nitrate on nitrite content of human saliva: possible relevance to in vivo formation of Nnitroso compounds. Food Cosmet. Toxicol., 14, 545–548 (1976).PubMedCrossRefGoogle Scholar
  51. Tripatara, P., Patel, N. S., Webb, A., Rathod, K., Lecomte, F. M., Mazzon, E., Cuzzocrea, S., Yaqoob, M. M., Ahluwalia, A., and Thiemermann, C., Nitrite-derived nitric oxide protects the rat kidney against ischemia/reperfusion injury in vivo: role for xanthine oxidoreductase. J. Am. Soc. Nephrol., 18, 570–580 (2007).PubMedCrossRefGoogle Scholar
  52. Vanin, A. F., Bevers, L. M., Slama-Schwok, A., and Van Faassen, E. E., Nitric oxide synthase reduces nitrite to NO under anoxia. Cell Mol Life Sci., 64, 96–103 (2007).PubMedCrossRefGoogle Scholar
  53. Webb, A., Bond, R., Mclean, P., Uppal, R., Benjamin, N., and Ahluwalia, A., Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemiareperfusion damage. Proc. Natl. Acad. Sci. USA, 101, 13683–13688 (2004).PubMedCrossRefGoogle Scholar
  54. Webb, A. J., Patel, N., Loukogeorgakis, S., Okorie, M., Aboud, Z., Misra, S., Rashid, R., Miall, P., Deanfield, J., Benjamin, N., Macallister, R., Hobbs, A. J., and Ahluwalia, A., Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension, 51, 784–90 (2008).PubMedCrossRefGoogle Scholar
  55. Weiss, S., Wilkins, R. W., and Haynes, F. W., The nature of the collapse induced by sodium nitrite. J. Clin. Invest., 16, 73–84 (1937).PubMedCrossRefGoogle Scholar
  56. Zhang, Z., Naughton, D. P., Blake, D. R., Benjamin, N., Stevens, C. R., Winyard, P. G., Symons, M. C., and Harrison, R., Human xanthine oxidase converts nitrite ions into nitric oxide (NO). Biochem. Soc. Trans., 25, 524S (1997).PubMedGoogle Scholar
  57. Zweier, J. L., Wang, P., Samouilov, A., and Kuppusamy, P., Enzyme-independent formation of nitric oxide in biological tissues. Nature Med., 1, 804–809 (1995).PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2009

Authors and Affiliations

  1. 1.Department of Physiology and PharmacologyDivision of Pharmacology Karolinska InstitutetStockholmSweden
  2. 2.Department of Physiology and PharmacologyDivision of Anesthesiology and Intensive Care Karolinska InstitutetStockholmSweden

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