Therapeutic effects of inorganic nitrate and nitrite in cardiovascular and metabolic diseases

Journal of Internal Medicine

Volumn 279, Issue 4, 2016, Pages 315-336

  Omar, S A ^a   Webb, A J ^b   Lundberg, J O ^a   Weitzberg, E ^a  

^a KAROLINSKA INSTITUTE   (Sweden)

^b KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Beetroot; Blood pressure; Ischaemia; Nitric oxide; Vasodilatation

Indexed keywords

NITRATE; NITRIC OXIDE; NITRIC OXIDE SYNTHASE; NITRITE; REACTIVE OXYGEN METABOLITE; NITRIC ACID DERIVATIVE;

ATHEROSCLEROSIS; BIOAVAILABILITY; CARDIOVASCULAR DISEASE; DIABETES MELLITUS; DRUG POTENCY; HUMAN; HYPERTENSION; INNATE IMMUNITY; LEAFY VEGETABLE; MEDITERRANEAN DIET; METABOLIC DISORDER; NONHUMAN; PRIORITY JOURNAL; REPERFUSION INJURY; REVIEW; SIGNAL TRANSDUCTION; THERAPY EFFECT; VASCULAR ENDOTHELIUM; ANIMAL; BIOSYNTHESIS; BLOOD PRESSURE; CARDIOVASCULAR DISEASES; CARDIOVASCULAR SYSTEM; DISEASE MODEL; DRUG EFFECTS; HEART FAILURE; HYPERTENSION, PULMONARY; LEUKOCYTE; METABOLIC DISEASES; METABOLISM; MYOCARDIAL INFARCTION; THROMBOCYTE ACTIVATION; VASODILATATION;

ANIMALS; BIOLOGICAL AVAILABILITY; BLOOD PRESSURE; CARDIOVASCULAR DISEASES; CARDIOVASCULAR SYSTEM; DISEASE MODELS, ANIMAL; HEART FAILURE; HUMANS; HYPERTENSION, PULMONARY; LEUKOCYTES; METABOLIC DISEASES; MYOCARDIAL INFARCTION; NITRATES; NITRIC OXIDE; NITRIC OXIDE SYNTHASE; NITRITES; PLATELET ACTIVATION; REPERFUSION INJURY; VASODILATION;

EID: 84961207584     PISSN: 09546820     EISSN: 13652796     Source Type: Journal    
DOI: 10.1111/joim.12441     Document Type: Review

References (183)

1. Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988; 333: 664-6.
2. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329: 2002-12.
3. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 1987; 84: 9265-9.
4. Ignarro LJ. Nitric oxide as a unique signaling molecule in the vascular system: a historical overview. J Physiol Pharmacol 2002; 53(4 Pt 1): 503-14.
5. Napoli C, Ignarro LJ. Nitric oxide and pathogenic mechanisms involved in the development of vascular diseases. Arch Pharm Res 2009; 32: 1103-8.
6. Blum M, Yachnin T, Wollman Y et al. Low nitric oxide production in patients with chronic renal failure. Nephron 1998; 79: 265-8.
7. Schmidt RJ, Baylis C. Total nitric oxide production is low in patients with chronic renal disease. Kidney Int 2000; 58: 1261-6.
8. Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 2008; 7: 156-67.
9. Weitzberg E, Lundberg JO. Novel aspects of dietary nitrate and human health. Annu Rev Nutr 2013; 33: 129-59.
10. Mitchell H, Shonle H, Grindley H. The origin of the nitrates in the urine. J Biol Chem 1916; 261-490.
11. Green LC, Tannenbaum SR, Goldman P. Nitrate synthesis in the germfree and conventional rat. Science 1981; 212: 56-8.
12. Green LC, Deluzuriaga KR, Wagner DA, Rand W, Istfan N, Young VR, Tannenbaum SR. Nitrate biosynthesis in Man. P Natl Acad Sci-Biol 1981; 78: 7764-8.
13. Furchgott RF, Zawadzki JV. The obligatory role of the endothelium in the relaxation of arterial smooth muscle by acetylcholine. Nature (London) 1980; 288: 373-6.
14. Forstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J 2012; 33: 829-37, 837a-837d.
15. Nathan C. Inducible nitric oxide synthase: what difference does it make? J Clin Invest 1997; 100: 2417-23.
16. Lundberg JO, Farkas-Szallasi T, Weitzberg E et al. High nitric oxide production in human paranasal sinuses. Nat Med 1995; 1: 370-3.
17. Shiva S, Wang X, Ringwood LA et al. Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis. Nat Chem Biol 2006; 2: 486-93.
18. Kleinbongard P, Dejam A, Lauer T et al. Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans. Free Radic Biol Med 2006; 40: 295-302.
19. Kim-Shapiro DB, Gladwin MT. Pitfalls in measuring NO bioavailability using NOx. Nitric Oxide 2015; 44: 1-2.
20. Landmesser U, Dikalov S, Price SR et al. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 2003; 111: 1201-9.
21. Chen CA, Wang TY, Varadharaj S et al. S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature 2010; 468: 1115-8.
22. Lundberg JON, Weitzberg E, Lundberg JM, Alving K. Intragastric nitric oxide production in humans: measurements in expelled air. Gut 1994; 35: 1543-6.
23. Zweier JL, Wang P, Samouilov A, Kuppusamy P. Enzyme-independent formation of nitric oxide in biological tissues. Nat Med 1995; 1: 804-9.
24. Benjamin N, O'Driscoll F, Dougall H, Duncan C, Smith L, Golden M, McKenzie H. Stomach NO synthesis. Nature 1994; 368: 502.
25. Butler AR, Feelisch M. Therapeutic uses of inorganic nitrite and nitrate: from the past to the future. Circulation 2008; 117: 2151-9.
26. Scheele CW. Chemische Abhandlung von der Luft und dem Feuer. M. Swederus, 1777.
27. Reichert ET, Mitchell SW. On the physiological action of potassium nitrite. Am J Med Sci 1880; 156: 158-80.
28. Hay M. Nitrite of sodium in the treatment of angina pectoris. Practitioner 1883; 30: 170-94.
29. Law WT. Sodium nitrite in the treatment of epilepsy. Practitioner 1882; 28: 420-4.
30. Wilkins RW, Haynes FW, Weiss S. The role of the venous system in circulatory collapse induced by sodium nitrite. J Clin Invest 1937; 16: 85-91.
31. Weiss S, Wilkins RW, Haynes FW. The nature of circulatory collapse induced by sodium nitrite. J Clin Invest 1937; 16: 73-84.
32. Omar SA, Artime E, Webb AJ. A comparison of organic and inorganic nitrates/nitrites. Nitric Oxide 2012; 26: 229-40.
33. Lloyd NL. A new kit for sodium nitrite-thiosulphate therapy in the treatment of acute cyanide poisoning. Br J Ind Med 1957; 14: 137.
34. Smith RP, Gosselin RE. Hydrogen sulfide poisoning. J Occup Med 1979; 21: 93-7.
35. Webb AJ, Patel N, Loukogeorgakis S et al. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension 2008; 51: 784-90.
36. Wagner DA, Schultz DS, Deen WM, Young VR, Tannenbaum SR. Metabolic fate of an oral dose of 15N-labeled nitrate in humans: effect of diet supplementation with ascorbic acid. Cancer Res 1983; 43: 1921-5.
37. Godfrey M, Majid DS. Renal handling of circulating nitrates in anesthetized dogs. Am J Physiol 1998; 275(1 Pt 2): F68-73.
38. Lundberg JO, Govoni M. Inorganic nitrate is a possible source for systemic generation of nitric oxide. Free Radic Biol Med 2004; 37: 395-400.
39. Spiegelhalder B, Eisenbrand G, Preussmann R. Influence of dietary nitrate on nitrite content of human saliva: possible relevance to in vivo formation of N-nitroso compounds. Food Cosmet Toxicol 1976; 14: 545-8.
40. Duncan C, Dougall H, Johnston P et al. Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate. Nat Med 1995; 1: 546-51.
41. Uusijarvi J, Eriksson K, Larsson AC et al. Effects of hyperbaric oxygen on nitric oxide generation in humans. Nitric Oxide 2015; 44: 88-97.
42. Hezel MP, Weitzberg E. The oral microbiome and nitric oxide homoeostasis. Oral Dis 2015; 21: 7-16.
43. Hunault CC, van Velzen AG, Sips AJ, Schothorst RC, Meulenbelt J. Bioavailability of sodium nitrite from an aqueous solution in healthy adults. Toxicol Lett 2009; 190: 48-53.
44. Bryan NS, Fernandez BO, Bauer SM et al. Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues. Nat Chem Biol 2005; 1: 290-7.
45. Carlsson S, Wiklund NP, Engstrand L, Weitzberg E, Lundberg JO. Effects of pH, nitrite, and ascorbic acid on nonenzymatic nitric oxide generation and bacterial growth in urine. Nitric Oxide 2001; 5: 580-6.
46. Peri L, Pietraforte D, Scorza G, Napolitano A, Fogliano V, 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 2005; 39: 668-81.
47. Gago B, Lundberg JO, Barbosa RM, Laranjinha J. Red wine-dependent reduction of nitrite to nitric oxide in the stomach. Free Radic Biol Med 2007; 43: 1233-42.
48. Bjorne H, Petersson J, Phillipson M, Weltzberg E, Holm L, Lundberg JO. Nitrite in saliva increases gastric mucosal blood flow and mucus thickness. J Clin Investig 2004; 113: 106-14.
49. Lundberg JO, Weitzberg E. Biology of nitrogen oxides in the gastrointestinal tract. Gut 2013; 62: 616-29.
50. Bernheim F, Dixon M. The reduction of nitrates in animal tissues. Biochem J 1928; 22: 125-34.
51. Jansson EA, Huang L, Malkey R et al. A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis. Nat Chem Biol 2008; 4: 411-7.
52. Omar S, Webb AJ. Nitrite reduction and cardiovascular protection. J Mol Cell Cardiol 2014; 73: 57-69.
53. Cosby K, Partovi KS, Crawford JH et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 2003; 9: 1498-505.
54. Shiva S, Huang Z, Grubina R et al. Deoxymyoglobin is a nitrite reductase that generates nitric oxide and regulates mitochondrial respiration. Circ Res 2007; 100: 654-61.
55. Tiso M, Tejero J, Basu S et al. Human neuroglobin functions as a redox-regulated nitrite reductase. J Biol Chem 2011; 286: 18277-89.
56. Li H, Hemann C, Abdelghany TM, El-Mahdy MA, Zweier JL. Characterization of the mechanism and magnitude of cytoglobin-mediated nitrite reduction and nitric oxide generation under anaerobic conditions. J Biol Chem 2012; 287: 36623-33.
57. Kozlov AV, Staniek K, Nohl H. Nitrite reductase activity is a novel function of mammalian mitochondria. FEBS Lett 1999; 454: 127-30.
58. Nohl H, Staniek K, Sobhian B, Bahrami S, Redl H, Kozlov AV. Mitochondria recycle nitrite back to the bioregulator nitric monoxide. Acta Biochim Pol 2000; 47: 913-21.
59. Godber BL, Doel JJ, Sapkota GP, Blake DR, Stevens CR, Eisenthal R, Harrison R. Reduction of nitrite to nitric oxide catalyzed by xanthine oxidoreductase. J Biol Chem 2000; 275: 7757-63.
60. Li H, Cui H, Kundu TK, Alzawahra W, Zweier JL. Nitric oxide production from nitrite occurs primarily in tissues not in the blood: critical role of xanthine oxidase and aldehyde oxidase. J Biol Chem 2008; 283: 17855-63.
61. Wang J, Fischer K, Zhao XJ et al. Novel function of sulfite oxidase as a nitrite reductase that generates nitric oxide. Free Radic Biol Med 2010; 49: S122-S122.
62. Gautier C, van Faassen E, Mikula I, Martasek P, Slama-Schwok A. Endothelial nitric oxide synthase reduces nitrite anions to NO under anoxia. Biochem Biophys Res Commun 2006; 341: 816-21.
63. Feelisch M, Fernandez BO, Bryan NS et al. Tissue processing of nitrite in hypoxia: an intricate interplay of nitric oxide-generating and -scavenging systems. J Biol Chem 2008; 283: 33927-34.
64. van Faassen EE, Babrami S, Feelisch M et al. Nitrite as regulator of hypoxic signaling in mammalian physiology. Med Res Rev 2009; 29: 683-741.
65. Samouilov A, Kuppusamy P, Zweier JL. Evaluation of the magnitude and rate of nitric oxide production from nitrite in biological systems. Arch Biochem Biophys 1998; 357: 1-7.
66. Lundberg JO, Weitzberg E. NO generation from nitrite and its role in vascular control. Arterioscler Thromb Vasc Biol 2005; 25: 915-22.
67. Ferguson SK, Hirai DM, Copp SW et al. Impact of dietary nitrate supplementation via beetroot juice on exercising muscle vascular control in rats. J Physiol 2013; 591(Pt 2): 547-57.
68. Oplander C, Volkmar CM, Paunel-Gorgulu A et al. Whole body UVA irradiation lowers systemic blood pressure by release of nitric oxide from intracutaneous photolabile nitric oxide derivates. Circ Res 2009; 105: 1031-40.
69. Paunel AN, Dejam A, Thelen S et al. Enzyme-independent nitric oxide formation during UVA challenge of human skin: characterization, molecular sources, and mechanisms. Free Radic Biol Med 2005; 38: 606-15.
70. Mowbray M, McLintock S, Weerakoon R, Lomatschinsky N, Jones S, Rossi AG, Weller RB. Enzyme-independent NO stores in human skin: quantification and influence of UV radiation. J Invest Dermatol 2009; 129: 834-42.
71. Liu D, Fernandez BO, Hamilton A et al. UVA irradiation of human skin vasodilates arterial vasculature and lowers blood pressure independently of nitric oxide synthase. J Invest Dermatol 2014; 134: 1839-46.
72. Katsuki S, Arnold W, Mittal C, Murad F. Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. J Cyclic Nucleotide Res 1977; 3: 23-35.
73. Hobbs AJ. Soluble guanylate cyclase: the forgotten sibling. Trends Pharmacol Sci 1997; 18: 484-91.
74. Cleeter MW, Cooper JM, Darley-Usmar VM, Moncada S, Schapira AH. Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. Implications for neurodegenerative diseases. FEBS Lett 1994; 345: 50-4.
75. Brown GC, Cooper CE. Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase. FEBS Lett 1994; 356: 295-8.
76. Boveris A, Costa LE, Poderoso JJ, Carreras MC, Cadenas E. Regulation of mitochondrial respiration by oxygen and nitric oxide. Ann N Y Acad Sci 2000; 899: 121-35.
77. Hess DT, Matsumoto A, Nudelman R, Stamler JS. S-nitrosylation: spectrum and specificity. Nat Cell Biol 2001; 3: E46-9.
78. Turko IV, Murad F. Protein nitration in cardiovascular diseases. Pharmacol Rev 2002; 54: 619-34.
79. Gow AJ, Farkouh CR, Munson DA, Posencheg MA, Ischiropoulos H. Biological significance of nitric oxide-mediated protein modifications. Am J Physiol Lung Cell Mol Physiol 2004; 287: L262-8.
80. Beckman JS, Beckman TW, Chen J, Marshall P, Freeman BA. Apparent hydroxyl radical production by peroxinitrite: implications for endothelial cell injury from nitric oxide. Proc Natl Acad Sci USA 1990; 87: 1620-4.
81. Malmstrom RE, Tornberg DC, Settergren G, Liska J, Angdin M, Lundberg JO, Weitzberg E. Endogenous nitric oxide release by vasoactive drugs monitored in exhaled air. Am J Respir Crit Care Med 2003; 168: 114-20.
82. Dejam A, Hunter CJ, Tremonti C et al. Nitrite infusion in humans and nonhuman primates. Endocrine Effects, Pharmacokinetics, and Tolerance Formation. Circulation, 2007; 116: 1821-31.
83. Kinsella JP, Cutter GR, Walsh WF et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med 2006; 355: 354-64.
84. Adhikari NK, Dellinger RP, Lundin S et al. Inhaled nitric oxide does not reduce mortality in patients with acute respiratory distress syndrome regardless of severity: systematic review and meta-analysis. Crit Care Med 2014; 42: 404-12.
85. Ghofrani HA, Osterloh IH, Grimminger F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov 2006; 5: 689-702.
86. Nguyen Dinh Cat A, Montezano AC, Burger D, Touyz RM. Angiotensin II, NADPH oxidase, and redox signaling in the vasculature. Antioxid Redox Signal 2013; 19: 1110-20.
87. Oak JH, Cai H. Attenuation of angiotensin II signaling recouples eNOS and inhibits nonendothelial NOX activity in diabetic mice. Diabetes 2007; 56: 118-26.
88. Dessy C, Saliez J, Ghisdal P et al. Endothelial beta3-adrenoreceptors mediate nitric oxide-dependent vasorelaxation of coronary microvessels in response to the third-generation beta-blocker nebivolol. Circulation 2005; 112: 1198-205.
89. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 1998; 273: 24266-71.
90. Kureishi Y, Luo Z, Shiojima I et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 2000; 6: 1004-10.
91. Antoniades C, Bakogiannis C, Leeson P et al. Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin-mediated endothelial nitric oxide synthase coupling. Circulation 2011; 124: 335-45.
92. Ivashchenko CY, Bradley BT, Ao Z, Leiper J, Vallance P, Johns DG. Regulation of the ADMA-DDAH system in endothelial cells: a novel mechanism for the sterol response element binding proteins, SREBP1c and -2. Am J Physiol Heart Circ Physiol 2010; 298: H251-8.
93. Ghofrani HA, D'Armini AM, Grimminger F et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013; 369: 319-29.
94. Scalbert A, Johnson IT, Saltmarsh M. Polyphenols: antioxidants and beyond. Am J Clin Nutr 2005; 81(1 Suppl): 215S-7S.
95. Laurent C, Chabi B, Fouret G et al. Polyphenols decreased liver NADPH oxidase activity, increased muscle mitochondrial biogenesis and decreased gastrocnemius age-dependent autophagy in aged rats. Free Radic Res 2012; 46: 1140-9.
96. Anter E, Thomas SR, Schulz E, Shapira OM, Vita JA, Keaney JF Jr. Activation of endothelial nitric-oxide synthase by the p38 MAPK in response to black tea polyphenols. J Biol Chem 2004; 279: 46637-43.
97. Larsen FJ, Ekblom B, Sahlin K, Lundberg JO, Weitzberg E. Effects of dietary nitrate on blood pressure in healthy volunteers. N Engl J Med 2006; 355: 2792-3.
98. Siervo M, Lara J, Ogbonmwan I, Mathers JC. Inorganic nitrate and beetroot juice supplementation reduces blood pressure in adults: a systematic review and meta-analysis. J Nutr 2013; 143: 818-26.
99. Weitzberg E, Hezel M, Lundberg JO. Nitrate-nitrite-nitric oxide pathway implications for anesthesiology and intensive care. Anesthesiology 2010; 113: 1460-75.
100. Vanhoutte PM. Endothelial dysfunction: the first step toward coronary arteriosclerosis. Circ J 2009; 73: 595-601.
101. Drexler H, Hornig B. Endothelial dysfunction in human disease. J Mol Cell Cardiol 1999; 31: 51-60.
102. Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000; 87: 840-4.
103. Stokes KY, Dugas TR, Tang Y, Garg H, Guidry E, Bryan NS. Dietary nitrite prevents hypercholesterolemic microvascular inflammation and reverses endothelial dysfunction. Am J Physiol Heart Circ Physiol 2009; 296: H1281-8.
104. Sindler AL, Fleenor BS, Calvert JW, Marshall KD, Zigler ML, Lefer DJ, Seals DR. Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging. Aging Cell 2011; 10: 429-37.
105. Heiss C, Meyer C, Totzeck M et al. Dietary inorganic nitrate mobilizes circulating angiogenic cells. Free Radic Biol Med 2012; 52: 1767-72.
106. Kapil V, Milsom AB, Okorie M et al. Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO. Hypertension 2010; 56: 274-81.
107. Lara J, Ashor AW, Oggioni C et al. Effects of inorganic nitrate and beetroot supplementation on endothelial function: a systematic review and meta-analysis. Eur J Nutr, 2015; [Epub ahead of print].
108. Ingram TE, Fraser AG, Bleasdale RA, Ellins EA, Margulescu AD, Halcox JP, James PE. Low-dose sodium nitrite attenuates myocardial ischemia and vascular ischemia-reperfusion injury in human models. J Am Coll Cardiol 2013; 61: 2534-41.
109. Rodriguez-Mateos A et al. Interaction of flavanol- and nitrate-related improvements of endothelial function. Free Radic Biol Med 2015; 80: 121-8.
110. Joris PJ, Mensink RP. Beetroot juice improves in overweight and slightly obese men postprandial endothelial function after consumption of a mixed meal. Atherosclerosis 2013; 231: 78-83.
111. Bahra M, Kapil V, Pearl V, Ghosh S, Ahluwalia A. Inorganic nitrate ingestion improves vascular compliance but does not alter flow-mediated dilatation in healthy volunteers. Nitric Oxide 2012; 26: 197-202.
112. Gilchrist M, Winyard PG, Aizawa K, Anning C, Shore A, Benjamin N. Effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes. Free Radic Biol Med 2013; 60: 89-97.
113. Densham B. The adjuvant action of the lactate ion on the vaso-dilator effect of sodium nitrite. J Physiol 1927; 63: 175-9.
114. Furchgott RF, Bhadrakom S. Reactions of strips of rabbit aorta to epinephrine, isopropylarterenol, sodium nitrite and other drugs. J Pharmacol Exp Ther 1953; 108: 129-43.
115. Modin A, Bjorne H, Herulf M, Alving K, Weitzberg E, Lundberg JO. Nitrite-derived nitric oxide: a possible mediator of 'acidic-metabolic' vasodilation. Acta Physiol Scand 2001; 171: 9-16.
116. Ingram TE, Pinder AG, Milsom AB, Rogers SC, Thomas DE, James PE. Blood vessel specific vaso-activity to nitrite under normoxic and hypoxic conditions. Adv Exp Med Biol 2009; 645: 21-5.
117. Gao X, Yang T, Liu M et al. NADPH Oxidase in the Renal Microvasculature Is a Primary Target for Blood Pressure-Lowering Effects by Inorganic Nitrate and Nitrite. Hypertension, 2015; 65: 161-70.
118. Liu M, Zollbrecht C, Peleli M, Lundberg JO, Weitzberg E, Carlstrom M. Nitrite-mediated renal vasodilatation is increased during ischemic conditions via cGMP-independent signaling. Free Radic Biol Med, 2015; 84: 154-60.
119. Lauer T, Preik M, Rassaf T, Strauer BE, Deussen A, Feelisch M, Kelm M. Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action. Proc Natl Acad Sci USA 2001; 98: 12814-9.
120. Maher AR, Milsom AB, Gunaruwan P et al. Hypoxic modulation of exogenous nitrite-induced vasodilation in humans. Circulation 2008; 117: 670-7.
121. Omar SA, Fok H, Tilgner KD et al. Paradoxical normoxia-dependent selective actions of inorganic nitrite in human muscular conduit arteries and related selective actions on central blood pressures. Circulation, 2015; 131: 381-9; discussion 389.
122. Beier S, Classen HG, Loeffler K, Schumacher E, Thoni H. Antihypertensive effect of oral nitrite uptake in the spontaneously hypertensive rat. Arzneimittelforschung 1995; 45: 258-61.
123. Classen HG, Stein-Hammer C, Thoni H. Hypothesis: the effect of oral nitrite on blood pressure in the spontaneously hypertensive rat. Does dietary nitrate mitigate hypertension after conversion to nitrite? J Am Coll Nutr 1990; 9: 500-2.
124. Kanematsu Y, Yamaguchi K, Ohnishi H et al. Dietary doses of nitrite restore circulating nitric oxide level and improve renal injury in L-NAME-induced hypertensive rats. Am J Physiol Renal Physiol 2008; 295: F1457-62.
125. Petersson J, Carlstrom M, Schreiber O et al. Gastroprotective and blood pressure lowering effects of dietary nitrate are abolished by an antiseptic mouthwash. Free Radic Biol Med 2009; 46: 1068-75.
126. Carlstrom M, Persson AE, Larsson E et al. Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension. Cardiovasc Res 2011; 89: 574-85.
127. Carlstrom M, Gao X, Patzak A, Sendeski M, Weitzberg E, Lundberg J, Persson AEG. Inorganic nitrite attenuates angiotensin ii induced contraction of renal microcirculation via xanthine oxidase-dependent no production. Nitric Oxide Biol Chem 2011; 24: S39-40.
128. Gao X, Yang T, Liu M et al. NADPH oxidase in the renal microvasculature is a primary target for blood pressure-lowering effects by inorganic nitrate and nitrite. Hypertension 2015; 65: 161-70.
129. Montenegro MF, Amaral JH, Pinheiro LC et al. Sodium nitrite downregulates vascular NADPH oxidase and exerts antihypertensive effects in hypertension. Free Radic Biol Med 2011; 51: 144-52.
130. Yang T, Peleli M, Zollbrecht C et al. Inorganic nitrite attenuates NADPH oxidase-derived superoxide generation in activated macrophages via a nitric oxide-dependent mechanism. Free Radic Biol Med 2015; 83: 159-66.
131. Carlstrom M, Liu M, Yang T et al. Cross-talk between nitrate-nitrite-NO and NO synthase pathways in control of vascular NO homeostasis. Antioxid Redox Signal, 2015; 23: 295-306.
132. Pinheiro LC, Montenegro MF, Amaral JH, Ferreira GC, Oliveira AM, Tanus-Santos JE. Increase in gastric pH reduces hypotensive effect of oral sodium nitrite in rats. Free Radic Biol Med 2012; 53: 701-9.
133. Bjorne H, Govoni M, Tornberg DC, Lundberg JO, Weitzberg E. Intragastric nitric oxide is abolished in intubated patients and restored by nitrite. Crit Care Med 2005; 33: 1722-7.
134. Weiss S, Ellis LB. Influence of sodium nitrite on the cardiovascular system and on renal activity. Arch Intern Med 1933; 52: 105-19.
135. Larsen FJ, Weitzberg E, Lundberg JO, Ekblom B. Dietary nitrate reduces maximal oxygen consumption while maintaining work performance in maximal exercise. Free Radic Biol Med, 2010; 48: 342-7.
136. Hobbs DA, George TW, Lovegrove JA. The effects of dietary nitrate on blood pressure and endothelial function: a review of human intervention studies. Nutr Res Rev 2013; 26: 210-22.
137. Kapil V, Haydar SMA, Pearl V, Lundberg JO, Weitzberg E, Ahluwalia A. Physiological role for nitrate-reducing oral bacteria in blood pressure control. Free Radic Biol Med 2013; 55: 93-100.
138. Kapil V, Khambata RS, Robertson A, Caulfield MJ, Ahluwalia A. Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: a randomized, phase 2, double-blind, placebo-controlled study. Hypertension 2015; 65: 320-7.
139. Appel LJ, Moore TJ, Obarzanek E et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med 1997; 336: 1117-24.
140. Sobko T, Marcus C, Govoni M, Kamiya S. Dietary nitrate in Japanese traditional foods lowers diastolic blood pressure in healthy volunteers. Nitric Oxide 2010; 22: 136-40.
141. Schulz R, Kelm M, Heusch G. Nitric oxide in myocardial ischemia/reperfusion injury. Cardiovasc Res 2004; 61: 402-13.
142. Webb A, Bond R, McLean P, Uppal R, Benjamin N, Ahluwalia A. Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. Proc Natl Acad Sci USA 2004; 101: 13683-8.
143. Duranski MR, Greer JJ, Dejam A et al. Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver. J Clin Invest 2005; 115: 1232-40.
144. Sinha SS, Shiva S, Gladwin MT. Myocardial protection by nitrite: evidence that this reperfusion therapeutic will not be lost in translation. Trends Cardiovasc Med 2008; 18: 163-72.
145. Calvert JW, Lefer DJ. Clinical translation of nitrite therapy for cardiovascular diseases. Nitric Oxide 2010; 22: 91-7.
146. Jung KH, Chu K, Ko SY et al. Early intravenous infusion of sodium nitrite protects brain against in vivo ischemia-reperfusion injury. Stroke 2006; 37: 2744-50.
147. Tripatara P, Patel NS, Webb A et al. Nitrite-derived nitric oxide protects the rat kidney against ischemia/reperfusion injury in vivo: role for xanthine oxidoreductase. J Am Soc Nephrol 2007; 18: 570-80.
148. Kumar D, Branch BG, Pattillo CB et al. Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis. Proc Natl Acad Sci USA 2008; 105: 7540-5.
149. Dezfulian C, Shiva S, Alekseyenko A et al. Nitrite therapy after cardiac arrest reduces reactive oxygen species generation, improves cardiac and neurological function, and enhances survival via reversible inhibition of mitochondrial complex I. Circulation 2009; 120: 897-905.
150. Shiva S, Sack MN, Greer JJ et al. Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J Exp Med 2007; 204: 2089-102.
151. Chouchani ET, Methner C, Nadtochiy SM et al. Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nat Med 2013; 19: 753-9.
152. Larsen FJ, Schiffer TA, Borniquel S, Sahlin K, Ekblom B, Lundberg JO, Weitzberg E. Dietary inorganic nitrate improves mitochondrial efficiency in humans. Cell Metab 2011; 13: 149-59.
153. Rassaf T, Totzeck M, Hendgen-Cotta UB, Shiva S, Heusch G, Kelm M. Circulating nitrite contributes to cardioprotection by remote ischemic preconditioning. Circ Res 2014; 114: 1601-10.
154. Rassaf T, Flogel U, Drexhage C, Hendgen-Cotta U, Kelm M, Schrader J. Nitrite reductase function of deoxymyoglobin: oxygen sensor and regulator of cardiac energetics and function. Circ Res 2007; 100: 1749-54.
155. Kenjale AA, Ham KL, Stabler T et al. Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease. J Appl Physiol 2011; 110: 1582-91.
156. Siddiqi N, Neil C, Bruce M et al. Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI). Eur Heart J 2014; 35: 1255-62.
157. Jones DA, Pellaton C, Velmurugan S et al. Randomized phase 2 trial of intra-coronary nitrite during acute myocardial infarction. Circ Res, 2015; 116: 437-47.
158. Baliga RS, MacAllister RJ, Hobbs AJ. New perspectives for the treatment of pulmonary hypertension. Br J Pharmacol 2011; 163: 125-40.
159. Gladwin MT, Hunter CJ, Dejam A et al. Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. Nat Med 2004; 10: 1122-7.
160. Blood AB, Schroeder HJ, Terry MH et al. Inhaled nitrite reverses hemolysis-induced pulmonary vasoconstriction in newborn lambs without blood participation. Circulation 2011; 123: 605-12.
161. Baliga RS, Milsom AB, Ghosh SM, Trinder SL, Macallister RJ, Ahluwalia A, Hobbs AJ. Dietary nitrate ameliorates pulmonary hypertension: cytoprotective role for endothelial nitric oxide synthase and xanthine oxidoreductase. Circulation 2012; 125: 2922-32.
162. Zuckerbraun BS, Shiva S, Ifedigbo E et al. Nitrite potently inhibits hypoxic and inflammatory pulmonary arterial hypertension and smooth muscle proliferation via xanthine oxidoreductase-dependent nitric oxide generation. Circulation 2010; 121: 98-109.
163. Pankey EA, Badejo AM, Casey DB et al. Effect of chronic sodium nitrite therapy on monocrotaline-induced pulmonary hypertension. Nitric Oxide 2012; 27: 1-8.
164. Rix PJ, Vick A, Attkins NJ et al. Pharmacokinetics, pharmacodynamics, safety, and tolerability of nebulized sodium nitrite (AIR001) following repeat-dose inhalation in healthy subjects. Clin Pharmacokinet 2015; 54: 261-72.
165. Jadert C, Petersson J, Massena S et al. Decreased leukocyte recruitment by inorganic nitrate and nitrite in microvascular inflammation and NSAID-induced intestinal injury. Free Radic Biol Med 2012; 52: 683-92.
166. Mathru M, Huda R, Solanki DR, Hays S, Lang JD. Inhaled nitric oxide attenuates reperfusion inflammatory responses in humans. Anesthesiology 2007; 106: 275-82.
167. Radomski MW, Palmer RM, Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet 1987; 2: 1057-8.
168. Richardson G, Hicks SL, O'Byrne S, Frost MT, Moore K, Benjamin N, McKnight GM. The ingestion of inorganic nitrate increases gastric S-nitrosothiol levels and inhibits platelet function in humans. Nitric Oxide 2002; 7: 24-9.
169. Velmurugan S, Kapil V, Ghosh SM et al. Antiplatelet effects of dietary nitrate in healthy volunteers: involvement of cGMP and influence of sex. Free Radic Biol Med 2013; 65: 1521-32.
170. Larsen FJ, Weitzberg E, Lundberg JO, Ekblom B. Effects of dietary nitrate on oxygen cost during exercise. Acta Physiol (Oxf) 2007; 191: 59-66.
171. Hoon MW, Johnson NA, Chapman PG, Burke LM. The effect of nitrate supplementation on exercise performance in healthy individuals: a systematic review and meta-analysis. Int J Sport Nutr Exerc Metab 2013; 23: 522-32.
172. Hernandez A, Schiffer TA, Ivarsson N et al. Dietary nitrate increases tetanic Ca2+ i and contractile force in mouse fast-twitch muscle. J Physiol 2012; 590: 3575-83.
173. Pellegrino D, Shiva S, Angelone T, Gladwin MT, Tota B. Nitrite exerts potent negative inotropy in the isolated heart via eNOS-independent nitric oxide generation and cGMP-PKG pathway activation. Biochim Biophys Acta 2009; 1787: 818-27.
174. Angelone T, Gattuso A, Imbrogno S, Mazza R, Tota B. Nitrite is a positive modulator of the Frank-Starling response in the vertebrate heart. Am J Physiol Regul Integr Comp Physiol 2012; 302: R1271-81.
175. Ashmore T, Fernandez BO, Branco-Price C et al. Dietary nitrate increases arginine availability and protects mitochondrial complex I and energetics in the hypoxic rat heart. J Physiol 2014; 592(Pt 21): 4715-31.
176. Zamani P, Rawat D, Shiva-Kumar P et al. Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation, 2015; 131: 371-80; discussion 380.
177. Zamani P, Rawat D, Kumar PS et al. Inorganic nitrate supplementation improves exercise capacity in subjects with HF with preserved EF - A pilot study. J Cardiac Fail 2014; 20: S4-S4.
178. Carlstrom M, Larsen FJ, Nystrom T, Hezel M, Borniquel S, Weitzberg E, Lundberg JO. Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice. Proc Natl Acad Sci USA 2010; 107: 17716-20.
179. Nystrom T, Ortsater H, Huang Z et al. Inorganic nitrite stimulates pancreatic islet blood flow and insulin secretion. Free Radic Biol Med 2012; 53: 1017-23.
180. Ohtake K, Nakano G, Ehara N, Sonoda K, Ito J, Uchida H, Kobayashi J. Dietary nitrite supplementation improves insulin resistance in type 2 diabetic KKA(y) mice. Nitric Oxide 2015; 44: 31-8.
181. Essawy SS, Abdel-Sater KA, Elbaz AA. Comparing the effects of inorganic nitrate and allopurinol in renovascular complications of metabolic syndrome in rats: role of nitric oxide and uric acid. Arch Med Sci 2014; 10: 537-45.
182. Jiang H, Torregrossa AC, Potts A, Pierini D, Aranke M, Garg HK, Bryan NS. Dietary nitrite improves insulin signaling through GLUT4 translocation. Free Radic Biol Med 2014; 67: 51-7.
183. Roberts LD, Ashmore T, Kotwica AO et al. Inorganic nitrate promotes the browning of white adipose tissue through the nitrate-nitrite-nitric oxide pathway. Diabetes 2015; 64: 471-84.