CONCLUDING REMARKS
The role of diet in the prevention and control of morbidity and premature mortality due to non-communicable diseases has been well established by vast population-based epidemiological studies carried out during the last decade.37 Nothing affects our health more than what we choose to eat. NO is essential for maintaining normal blood pressure, preventing adhesion of blood cells to the endothelium, and preventing platelet aggregation; it may, therefore, be argued that this single abnormality – the inability to generate NO – puts us at risk for diseases that plague us later in life, such as atherosclerosis, myocardial infarction, stroke, and peripheral vascular disease. Therefore developing strategies and new technologies designed to restore NO availability is essential for inhibiting the progression of certain common chronic diseases. NO should be a primary consideration in anti-aging medicine. We now have the tools and resources for diagnosing NO insufficiency and repleting NO in patients.
REFERENCES
1.Stuehr DJ, Marletta MA. Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide. Proc Natl Acad Sci U S A. 1985;82:7738-7742.
2.Hibbs JB Jr, Taintor RR, Vavrin Z. Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science. 1987;235:473-476.
3.Arnold WP, Mittal CK, Katsuki S, Murad F. Nitric oxide activates guanylate cyclase and increases guanosine 3':5'-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci U S A. 1977;74:3203-3207.
4.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 U S A. 1987;84:9265-9269.
5.Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373-376.
6.Garthwaite J, Charles SL, Chess-Williams R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature. 1988;336:385-388.
7.Schulman SP, Becker LC, Kass DA, et al. L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA. 2006;295:58-64.
8.van der Loo B, Labugger R, Skepper JN, et al. Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med. 2000;192:1731-1744.
9.Pie JE, Baek SY, Kim HP, et al. Age-related decline of inducible nitric oxide synthase gene expression in primary cultured rat hepatocytes. Mol Cells. 2002;13:399-406.
10.Zhou XJ, Vaziri ND, Zhang J, Wang HW, Wang XQ. Association of renal injury with nitric oxide deficiency in aged SHR: prevention by hypertension control with AT1 blockade. Kidney Int. 2002;62:914-921.
11.Berkowitz DE, White R, Li D, et al. Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation. 2003;108:2000-2006.
12.Taddei S, Virdis A, Ghiadoni L, et al. Age-related reduction of NO availability and oxidative stress in humans. Hypertension. 2001;38:274-279.
13.Egashira K, Inou T, Hirooka Y, et al. Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans. Circulation. 1993;88:77-81.
14.Vita JA, Treasure CB, Nabel EG, et al. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation. 1990;81:491-497.
15.Gerhard M, Roddy MA, Creager SJ, Creager MA. Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans. Hypertension. 1996;27:849-853.
16.Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(23 Suppl 1):III27-32.
17.Schächinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000;101:1899-1906.
18.Halcox JP, Schenke WH, Zalos G, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002;106:653-658.
19.Bugiardini R, Manfrini O, Pizzi C, Fontana F, Morgagni G. Endothelial function predicts future development of coronary artery disease: a study of women with chest pain and normal coronary angiograms. Circulation. 2004;109:2518-2523.
20.Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation. 2005;111:363-368.
21.Elrod JW, Calvert JW, Gundewar S, Bryan NS, Lefer DJ. Nitric oxide promotes distant organ protection: evidence for an endocrine role of nitric oxide. Proc Natl Acad Sci U S A. 2008;105:11430-11435.
22.Bryan NS, Rassaf T, Maloney RE, et al. Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature and kinetics in vivo. Proc Natl Acad Sci U S A. 2004;101:4308-4313.
23.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;1:290-297.
24.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;283:33927-339234.
25.Kleinbongard P, Dejam A, Lauer T, et al. Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals. Free Radic Biol Med. 2003;35:790-796.
26.Bryan NS, Calvert JW, Elrod JW, Gundewar S, Ji SY, Lefer DJ. Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury. Proc Natl Acad Sci U S A. 2007;104:19144-19149.
27.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;204:2089-20102.
28.Hunter CJ, Dejam A, Blood AB, et al. Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. Nat Med. 2004;10:1122-1127.
29.Hardwick JB, Tucker AT, Wilks M, Johnston A, Benjamin N. A novel method for the delivery of nitric oxide therapy to the skin of human subjects using a semi-permeable membrane. Clin Sci (Lond). 2001;100:395-400.
30.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;1:546-551.
31.Björne H H, Petersson J, Phillipson M, Weitzberg E, Holm L, Lundberg JO. Nitrite in saliva increases gastric mucosal blood flow and mucus thickness. J Clin Invest. 2004;113:106-114. Erratum in: J Clin Invest. 2004;113:490.
32.Tang Y, Garg H, Geng YJ, Bryan NS. Nitric oxide bioactivity of traditional Chinese medicines used for cardiovascular indications. Free Radic Biol Med. 2009;47:835-840.
33.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.
34.Bryan NS. Nitrite in nitric oxide biology: cause or consequence? A systems-based review. Free Radic Biol Med. 2006;41:691-701.
35.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;355:2792-2793.
36.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;51:784-790.
37.Diet, nutrition, and the prevention of chronic diseases. Report of a WHO Study Group. Geneva,