Abstract
Having high blood pressure puts you at risk for heart disease and stroke, which are leading causes of death in the USA and worldwide. One out of every three Americans has hypertension, and it is estimated that despite aggressive treatment with medications, only about half of those medicated have managed blood pressure. Recent discoveries of the oral microbiome that reduces inorganic nitrate to nitrite and nitric oxide provide a new therapeutic target for the management of hypertension. The presence or absence of select and specific bacteria may determine steady-state blood pressure levels. Eradication of oral bacteria through antiseptic mouthwash or overuse of antibiotics causes blood pressure to increase. Allowing recolonization of nitrate- and nitrite-reducing bacteria can normalize blood pressure. This review will provide evidence of the link between oral microbiota and the production of nitric oxide and regulation of systemic blood pressure. Management of systemic hypertension through maintenance of the oral microbiome is a completely new paradigm in cardiovascular medicine.
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References
Papers of Particular Interest, Published Recently, Have Been Highlighted as: • Of importance•• Of major importance
Kearney PM, et al. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365(9455):217–23.
Go AS, et al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation. 2014;129(3):e28–e292.
Bum EN, et al. Anticonvulsant properties of the methanolic extract of Cyperus Articulatus (Cyperaceae). J Ethnopharmacol. 2001;76(2):145–50.
Franklin SS. Cardiovascular risks related to increased diastolic, systolic and pulse pressure. An epidemiologist’s point of view. Pathol Biol (Paris). 1999;47(6):594–603.
Franklin SS, et al. Predominance of isolated systolic hypertension among middle-aged and elderly US hypertensives: analysis based on National Health and Nutrition Examination Survey (NHANES) III. Hypertension. 2001;37(3):869–74.
Chobanian AV, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206–52.
Hsu CY, et al. Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease. Arch Intern Med. 2005;165(8):923–8.
Levy D, et al. The progression from hypertension to congestive heart failure. JAMA. 1996;275(20):1557–62.
Vasan RS, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med. 2001;345(18):1291–7.
Organization, WH. World Health Statistics. Luxembourg: World Health Organization; 2015.
Wright Jr JT, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103–16.
Wang YR, Alexander GC, Stafford RS. Outpatient hypertension treatment, treatment intensification, and control in Western Europe and the United States. Arch Intern Med. 2007;167(2):141–7.
Cutler JA, et al. Trends in hypertension prevalence, awareness, treatment, and control rates in United States adults between 1988–1994 and 1999–2004. Hypertension. 2008;52(5):818–27.
•• Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetycholine. Nature. 1980;288(5789):373–6. The original discovery of an endothelium derived relaxing factor that led to Nobel Prize
• Ignarro LJ, et al. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A. 1987;84:9265–9. The identification of EDRF as nitric oxide which led to Nobel Prize for Dr. Ignarro
• Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327(6122):524–6. First demonstration that EDRF is nitric oxide
Antonakoudis G, et al. Blood pressure control and cardiovascular risk reduction. Hippokratia. 2007;11(3):114–9.
Lieberman EH, et al. Flow-induced vasodilation of the human brachial artery is impaired in patients <40 years of age with coronary artery disease. Am J Cardiol. 1996;78(11):1210–4.
Ludmer PL, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986;315(17):1046–51.
Napoli C, Ignarro LJ. Nitric oxide and pathogenic mechanisms involved in the development of vascular diseases. Arch Pharm Res. 2009;32(8):1103–8.
Creager MA, et al. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990;86(1):228–34.
Celermajer DS, et al. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993;88(5 Pt 1):2149–55.
Forstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch. 2010;459(6):923–39.
Robles Alonso V, Guarner F. Linking the gut microbiota to human health. Br J Nutr. 2013;109(Suppl 2):S21–6.
Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov. 2008;7(8):156–67.
Lundberg JO, et al. Nitrate, bacteria and human health. Nat Rev Microbiol. 2004a;2(7):593–602.
Nunez De Gonzalez, M.T., et al., Survey of residual nitrite and nitrate in conventional and organic/natural/uncured/indirectly cured meats available at retail in the United States. J Agric Food Chem, 2012. 60(15): p. 3981–3990.
Nunez De Gonzalez, M.T., et al., A survey of nitrate and nitrite concentrations in conventional and organic-labeled raw vegetables at retail. J Food Sci, 2015. 80(5): p. C942–C949.
Kelm M. Nitric oxide metabolism and breakdown. Biochim Biophys Acta. 1999;1411:273–89.
• Bryan NS, et al. Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues. Nat Chem Biol. 2005;1(5):290–7. Report showing evidence that nitrite acts as a signaling molecule independent of its reduction to nitric oxide
Zweier JL, et al. Enzyme-independent formation of nitric oxide in biological tissues. Nat Med. 1995;1(8):804–9.
Lundberg JO, et al. Intragastric nitric oxide production in humans: measurements in expelled air. Gut. 1994;35(11):1543–6.
Benjamin N, et al. Stomach NO synthesis. Nature. 1994;368(6471):502.
• Bryan NS, Ivy JL. Inorganic nitrite and nitrate: evidence to support consideration as dietary nutrients. Nutr Res. 2015;35(8):643–54. Comprehensive human evidence presented for establishment of dietary guidelines for nitrite and nitrate
• Bryan NS, Loscalzo J. Nitrite and nitrate in human health and disease. In: Bendich A, editor. Nutrition and health. New York: Humana Press; 2011. First edited book on the therapeutic and safety profile of nitrite and nitrate
•• Duncan C, et al. Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate. Nat Med. 1995a;1(6):546–51. First demonstration that inorganic nitrate could be metabolized to nitrite and nitric oxide by oral nitrate reducing bacteria
Lundberg JO, Govoni M. Inorganic nitrate is a possible source for systemic generation of nitric oxide. Free Radic Biol Med. 2004;37(3):395–400.
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(6):545–8.
Hunault CC, et al. Bioavailability of sodium nitrite from an aqueous solution in healthy adults. Toxicol Lett. 2009;190(1):48–53.
Duncan C, et al. Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate. Nat Med. 1995b;1(6):546–51.
Lundberg J, et al. Nitrate, bacteria, and human health. Nat Rev Microbiol. 2004b;2:593–602.
Doel J, et al. Evaluation of bacterial nitrate reduction in the human oral cavity. Eur J Oral Sci. 2005;113:14–9.
Hyde ER, et al. Metagenomic analysis of nitrate-reducing bacteria in the oral cavity: implications for nitric oxide homeostasis. PLoS One. 2014;9(3):e88645.
• Bryan NS, et al. Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury. Proc Natl Acad Sci U S A. 2007;104(48):19144–9. Study showing dietary nitrite and nitrate could protect the heart from injury from heart attack
Bryan NS, et al. Dietary nitrite restores NO homeostasis and is cardioprotective in endothelial nitric oxide synthase-deficient mice. Free Radic Biol Med. 2008;45(4):468–74.
Webb AJ, et al. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension. 2008;51(3):784–90.
Carlstrom M, et al. Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice. PNAS. 2010;107(41):17716–20.
Carlstrom M, et al. Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension. Cardiovasc Res. 2011;89(3):574–85.
Kleinbongard P, et al. Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals. Free Radic Biol Med. 2003;35(7):790–6.
Bryan NS. Nitrite in nitric oxide biology: cause or consequence? A systems-based review. Free Radic Biol Med. 2006;41(5):691–701.
Angelo M, Singel DJ, Stamler JS. An S-nitrosothiol (SNO) synthase function of hemoglobin that utilizes nitrite as a substrate. Proc Natl Acad Sci U S A. 2006;103(22):8366–71.
Furchgott RF, Bhadrakom S. Reactions of strips of rabbit aorta to epinephrine, isopropylarterenol, sodium nitrite and other drugs. J Pharmacol Exp Ther. 1953;108(2):129–43.
Cosby K, et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med. 2003a;9:1498–505.
Tannenbaum SR, et al. Nitrite in human saliva. Its possible relationship to nitrosamine formation. J Natl Cancer Inst. 1974;53(1):79–84.
van Maanen JM, van Geel AA, Kleinjans JC. Modulation of nitrate-nitrite conversion in the oral cavity. Cancer Detect Prev. 1996;20(6):590–6.
Walters CL, Casselden RJ, Taylor AM. Nitrite metabolism by skeletal muscle mitochondria in relation to haem pigments. Biochim Biophys Acta. 1967;143(2):310–8.
Kozlov AV, Staniek K, Nohl H. Nitrite reductase activity is a novel function of mammalian mitochondria. FEBS Lett. 1999;454(1–2):127–30.
Cosby K, et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med. 2003b;9(12):1498–505.
Li H, et al. Characterization of the effects of oxygen on xanthine oxidase-mediated nitric oxide formation. J Biol Chem. 2004;279(17):16939–46.
Webb A, et al. Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. Proc Natl Acad Sci U S A. 2004a;101(37):13683–8.
Bryan NS, 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(12):4308–13.
Duranski MR, et al. Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver. J Clin Invest. 2005;115(5):1232–40.
Pluta RM, et al. Nitrite infusions to prevent delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage. JAMA. 2005;293(12):1477–84.
Hunter CJ, et al. Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. Nat Med. 2004;10:1122–7.
Hardwick JB, et al. 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(4):395–400.
Bjorne HH, et al. Nitrite in saliva increases gastric mucosal blood flow and mucus thickness. J Clin Invest. 2004;113(1):106–14.
Tsuchiya K, et al. Nitrite is an alternative source of NO in vivo. Am J Physiol Heart Circ Physiol. 2005;288(5):H2163–70.
Kleinbongard P, et al. Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans. Free Radic Biol Med. 2006;40(2):295–302.
Petersson J, et al. Gastroprotective and blood pressure lowering effects of dietary nitrate are abolished by an antiseptic mouthwash. Free Radic Biol Med. 2009;46(8):1068–75.
Webb, A., et al. Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. Proc Natl Acad Sci USA. 2004b. 101(13683–13688).
Hendgen-Cotta UB, et al. Dietary nitrate supplementation improves revascularization in chronic ischemia. Circulation. 2012;126(16):1983–92.
Woessner M, et al. A stepwise reduction in plasma and salivary nitrite with increasing strengths of mouthwash following a dietary nitrate load. Nitric Oxide. 2016;54:1–7.
Larsen FJ, et al. Effects of dietary nitrate on blood pressure in healthy volunteers. N Engl J Med. 2006;355(26):2792–3.
•• Kapil V, et al. Physiological role for nitrate-reducing oral bacteria in blood pressure control. Free Radic Biol Med. 2013;55:93–100. Study demonstrating that oral nitrate reducing bacteria can affect systemic blood pressure
McDonagh ST, et al. The effects of chronic nitrate supplementation and the use of strong and weak antibacterial agents on plasma nitrite concentration and exercise blood pressure. Int J Sports Med. 2015;36(14):1177–85.
Pinheiro LC, et al. Oral nitrite circumvents antiseptic mouthwash-induced disruption of enterosalivary circuit of nitrate and promotes nitrosation and blood pressure lowering effect. Free Radic Biol Med. 2016;101:226–35.
Joshipura K, Ritchie C, Douglass C. Strength of evidence linking oral conditions and systemic disease. Compend Contin Educ Dent Suppl. 2000;30:12–23. quiz 65
Torregrossa AC, Aranke M, Bryan NS. Nitric oxide and geriatrics: implications in diagnostics and treatment of the elderly. J Geriatr Cardiol. 2011;8:230–42.
Bryan NS, Bian K, Murad F. Discovery of the nitric oxide signaling pathway and targets for drug development. Front Biosci. 2009;14:1–18.
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Dr. Bryan reports personal fees and other from HumanN, Inc. In addition, he has a patent 8,298,589 with royalties paid to University of Texas, a patent 8,303,995 with royalties paid to University of Texas, a patent 8,435,570 with royalties paid to University of Texas, a patent 8,962,038 with royalties paid to University of Texas, a patent 9,119,823 with royalties paid to University of Texas, and a patent 9,241,999 with royalties paid to University of Texas. XXX declare no conflicts of interest relevant to this manuscript. Drs. Tribble and Angelov declare no conflicts of interest relevant to this manuscript.
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This article is part of the Topical Collection on Gut Microbiome, Sympathetic Nervous System, and Hypertension
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Bryan, N.S., Tribble, G. & Angelov, N. Oral Microbiome and Nitric Oxide: the Missing Link in the Management of Blood Pressure. Curr Hypertens Rep 19, 33 (2017). https://doi.org/10.1007/s11906-017-0725-2
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DOI: https://doi.org/10.1007/s11906-017-0725-2