Nitric oxide and endothelial function: the lining of your blood vessels
Nitric oxide (NO) is a short-lived gas that the thin lining of your blood vessels, the endothelium, releases to tell the muscle in the vessel wall to relax. That relaxation widens the artery, eases blood flow and helps set your blood pressure moment to moment. Your body makes NO by two routes: an enzyme pathway that uses the amino acid L-arginine, and a dietary route that turns the nitrate in leafy greens and beetroot into nitrite and then NO, with help from bacteria on your tongue. The strongest, best-evidenced ways to support this system are regular exercise and a vegetable-rich diet, not supplements.
Key facts
- The endothelium-derived relaxing factor was identified as nitric oxide in the 1980s, work that earned Furchgott, Ignarro and Murad the 1998 Nobel Prize in Physiology or Medicine.1
- A meta-analysis of randomised trials found dietary nitrate (mostly beetroot juice) lowered systolic blood pressure by about 4.4 mmHg on average (95% CI 2.8 to 5.9).2
- In a 4-week trial in 68 people with hypertension, daily beetroot juice cut both clinic and 24-hour systolic pressure by roughly 7.7 mmHg and improved measured endothelial function, while nitrate-stripped juice did nothing.3
- An antibacterial mouthwash can wipe out the tongue bacteria that start this process, blocking most of the nitrite rise and the blood pressure fall.45
What nitric oxide actually does
Picture a blood vessel as a tube with three layers. The innermost is a single sheet of cells, the endothelium, that lines every artery, vein and capillary in the body. Far from being passive plumbing, this lining is an active organ: it senses the flow passing over it and releases chemical signals that control the diameter of the vessel. The most important of those signals is nitric oxide.
When the endothelium releases NO, the gas diffuses into the layer of smooth muscle wrapped around the vessel. There it switches on an enzyme called soluble guanylate cyclase, which produces a messenger (cyclic GMP) that makes the muscle relax. The vessel widens, resistance to flow drops, and blood moves more easily. This is vasodilation, and it happens continuously to match blood supply to demand, for example opening arteries to working muscle or to the heart itself.1
Because so many small arteries are quietly dilating at any moment, NO is one of the main brakes on blood pressure. It also keeps the vessel lining smooth and non-sticky, discouraging platelets from clumping and white cells from latching on, both early steps in the furring-up process of atherosclerosis. When the endothelium makes plenty of NO, the system runs well. When it makes too little, a state called endothelial dysfunction, pressure tends to creep up and the groundwork for cardiovascular disease is laid. This sits behind much of what we cover in our health library on heart and circulation.
The two pathways that make it
Your body produces NO by two separate routes, and they behave differently. Understanding both is the key to understanding why beetroot and exercise help, and why most supplements disappoint.
The L-arginine / eNOS pathway
The classic route runs inside the endothelial cell. An enzyme called endothelial nitric oxide synthase (eNOS) takes the amino acid L-arginine and converts it into NO, releasing L-citrulline as a by-product. The reaction needs oxygen and a helper molecule called tetrahydrobiopterin (BH4). This is the pathway that responds to the drag of blood flowing over the lining, known as shear stress, which is why moving more blood through your arteries, as in exercise, is such a powerful stimulus.1
The dietary nitrate / nitrite / NO pathway
The second route does not need eNOS at all and comes from food. Green leafy vegetables and beetroot are rich in inorganic nitrate. After you eat them, nitrate is absorbed, then concentrated in your saliva. Bacteria living on the back of your tongue reduce that nitrate to nitrite, which you swallow. In the acidic stomach and in tissues short of oxygen, nitrite is converted onward to NO. This is sometimes called the enterosalivary pathway, and it matters most exactly when the oxygen-dependent eNOS route struggles, such as in hard-working or poorly perfused tissue.4
The two systems are complementary. The eNOS route is the everyday workhorse; the dietary route is a back-up that you can top up through diet. Critically, the dietary route depends on those tongue bacteria, which is the hinge on which the mouthwash story turns.
Why endothelial function declines
Endothelial function is not fixed. It can be measured in research settings, most often by flow-mediated dilation (FMD): an ultrasound technique that checks how much the brachial artery in the arm widens after blood flow is briefly restricted and released. A healthy artery dilates well; a dysfunctional one barely budges. FMD falls steadily with age and with each cardiovascular risk factor, and a lower FMD independently predicts future heart attacks and strokes, adding information beyond the usual risk factors.6
Several forces drag the system down:
- Ageing. NO production falls and the lining becomes less responsive with each decade.
- Inactivity. Without the regular pulse of shear stress from exercise, eNOS activity and NO output decline.
- Risk factors. High blood pressure, high LDL cholesterol, smoking, diabetes and obesity all raise oxidative stress in the vessel wall.
- eNOS uncoupling. Under heavy oxidative stress, and when BH4 runs short, the eNOS enzyme malfunctions and starts producing superoxide, a damaging free radical, instead of NO. The very enzyme meant to protect the vessel then adds to the harm. This mechanism is well described in animal and laboratory studies of ageing vessels and is best labelled mechanistic rather than proven to drive outcomes in people.7
Evidence strength: that NO is the endothelium-derived relaxing factor, and that eNOS makes it from L-arginine, is settled biochemistry recognised by a Nobel Prize.1 That low FMD predicts cardiovascular events is supported by meta-analysis of prospective cohorts.6 The finer molecular account of eNOS uncoupling is solid mechanistically but is not the same as proof that any given supplement fixes it.
The dietary nitrate evidence
This is the part of the field with genuinely decent human data. The story began with a 2008 study led by Andrew Webb and Amrita Ahluwalia in London, published in Hypertension. Healthy volunteers who drank 500 mL of beetroot juice had their blood pressure fall by up to about 10.4/8 mmHg around three hours later, tracking the rise in plasma nitrite.4 The same group then tested whether this held up in people who actually have high blood pressure.
In that 2015 trial, also in Hypertension, Vikas Kapil and colleagues randomised 68 adults with hypertension to 250 mL of beetroot juice daily or to nitrate-depleted juice (identical taste, nitrate removed) for four weeks. The active group saw clinic systolic pressure drop by 7.7 mmHg and 24-hour ambulatory systolic pressure by the same 7.7 mmHg, with measured improvements in endothelial function (FMD up by 1.0 percent) and arterial stiffness. The placebo juice did nothing, which neatly shows the effect is the nitrate, not the beetroot.3
Pooling the trials, a 2013 meta-analysis by Mario Siervo and colleagues in the Journal of Nutrition found that inorganic nitrate and beetroot juice lowered systolic blood pressure by an average of 4.4 mmHg (95% CI 2.8 to 5.9) across studies.2 A drop of that size, sustained, is clinically meaningful at a population level.
| Study | Design and population | Main result |
|---|---|---|
| Webb et al., 20084 | Acute crossover, healthy volunteers, 500 mL beetroot juice | Peak fall up to about 10.4/8 mmHg at ~3 h; abolished if saliva was spat out |
| Kapil et al., 20153 | RCT, 68 adults with hypertension, 250 mL daily for 4 weeks | Clinic and 24-h systolic both down ~7.7 mmHg; FMD improved; placebo juice inert |
| Siervo et al., 20132 | Meta-analysis of RCTs | Systolic blood pressure lowered by ~4.4 mmHg on average |
| Govoni et al., 20085 | Crossover, antibacterial mouthwash vs none | Oral nitrate reduction cut ~90 percent; plasma nitrite rise blocked |
What about exercise performance?
Dietary nitrate also became popular with athletes because it reduces the oxygen cost of submaximal exercise, meaning you can do the same work for slightly less effort. A 2025 umbrella review in Sports Medicine by Poon and colleagues, gathering 20 meta-analyses, found a small but real benefit for endurance capacity (time to exhaustion, standardised mean difference about 0.33), with weaker and less consistent effects on time-trial performance. Benefits were clearer with a dose of at least roughly 6 to 8 mmol of nitrate per day taken for several days. The authors flagged that the quality of the underlying reviews was often low, so this is promising rather than definitive.8 For everyday health, the blood pressure data matter more than the marginal sporting edge.
The mouthwash problem
Here is the twist that makes the dietary pathway so distinctive: it runs through bacteria on your tongue. If you remove those bacteria, you remove the benefit. Webb's 2008 study proved the point elegantly. When a second group of volunteers refrained from swallowing their saliva for three hours after the beetroot, the rise in nitrite and the fall in blood pressure simply did not happen.4
Antibacterial mouthwash does the same thing chemically. In a study by Govoni and colleagues, a chlorhexidine antibacterial rinse reduced oral conversion of nitrate to nitrite by around 90 percent and blunted the expected rise in plasma nitrite.5 Later work has linked regular use of antibacterial mouthwash to small rises in blood pressure, on the order of a few mmHg, by interrupting this same enterosalivary cycle.4 The everyday lesson is simple, and is set out in the safety box below.
If you are using dietary nitrate (beetroot juice or plenty of leafy greens) to support blood pressure, avoid antibacterial mouthwash, at least around the same time, because it can wipe out the tongue bacteria that start the process and blunt the effect.5 This is not a reason to neglect oral hygiene: brushing, flossing and treating gum disease remain important. The point is specifically about routine antibacterial rinsing, not normal tooth-brushing.
L-arginine and L-citrulline: the honest read
If eNOS makes NO from L-arginine, it seems logical that swallowing L-arginine should raise NO. In practice it is messier. Oral L-arginine is heavily broken down in the gut and liver before it reaches the bloodstream, so the dose that gets through is modest, and the body also has competing enzymes that consume it. L-citrulline, found in watermelon, is in some ways a better bet because the kidneys convert it efficiently into L-arginine, raising blood arginine levels more reliably than arginine itself.
The trial evidence is real but modest. Meta-analyses of randomised trials report small reductions in blood pressure and some improvement in endothelial measures with L-citrulline and L-arginine, generally at higher daily doses (around 6 g or more), and most clearly in people who already have raised blood pressure, arterial stiffness or specific conditions.9 These are not transformative effects, the studies are often small and short, and the supplement market wildly overstates them. Treat L-citrulline as a possible minor add-on, not a substitute for diet and exercise, and be sceptical of any product promising dramatic NO boosting. Our stack builder can help you weigh whether an add-on like this earns its place, and our insights archive explains how to read supplement claims critically.
This is the most important safety point on the page. If you take nitrate medication for angina (such as glyceryl trinitrate, isosorbide mononitrate or dinitrate) or a PDE5 inhibitor (sildenafil, tadalafil, vardenafil, for erectile dysfunction or pulmonary hypertension), be cautious with NO-boosting approaches and do not combine these drug classes with each other. Both work by amplifying the NO/cGMP system, and together they can cause a dangerous, sometimes life-threatening drop in blood pressure. Large doses of beetroot juice or L-citrulline could in theory add to this. If you are on any of these medicines, talk to your GP or pharmacist before starting beetroot juice or NO supplements.
Exercise: the strongest lever
If you want to improve endothelial function, the best-supported intervention is not in a bottle. Each time you exercise, more blood flows through your arteries, and the increased shear stress on the lining is the natural trigger for eNOS to make NO. Done repeatedly, this raises eNOS activity and NO availability and improves how well your vessels dilate.
The human evidence is consistent. Meta-analyses of randomised trials show that regular aerobic exercise improves flow-mediated dilation, with combined aerobic and resistance training also helping, and the gains are seen in middle-aged and older adults, exactly the groups whose endothelial function has started to slide.10 Unlike a supplement, exercise also lowers blood pressure, improves cholesterol and insulin sensitivity and reduces hard cardiovascular outcomes. Dietary nitrate and exercise are not rivals: they act on overlapping parts of the same NO system and stack sensibly.
Practical, food-first steps
The takeaways here are cheap, safe for most people and supported by the best evidence in the field. Food first, supplements last.
- Eat nitrate-rich vegetables daily. Rocket, spinach, lettuce, beetroot, celery and kale are among the richest sources. A portion of leafy greens or a small glass of beetroot juice provides a meaningful nitrate dose.
- Move most days. Regular aerobic activity, brisk walking upward, is the single strongest stimulus to endothelial NO. Add some resistance work.
- Reconsider antibacterial mouthwash if you use it routinely, especially if you are working on your blood pressure. Keep brushing and flossing.
- Do not rely on NO supplements. If you try L-citrulline, see it as a marginal extra at an adequate dose, not the main event.
- Mind the medication interactions above if you take nitrates for angina or PDE5 inhibitors.
A note on nitrate and cancer worries. The nitrate in vegetables is not the same risk as the nitrite added to processed meats. Vegetables carry vitamin C and other antioxidants that block formation of the harmful nitrosamines that can arise when nitrite reacts with meat proteins. Large cohort studies and UK food safety guidance distinguish the two: naturally occurring vegetable nitrate is not linked to the cancer risk associated with processed meat.1112 Eat the greens.
- I take a nitrate medicine for angina (or a PDE5 inhibitor): is it safe for me to drink beetroot juice or try an NO supplement?
- My blood pressure is borderline: would a vegetable-rich, higher-nitrate diet be a reasonable first step alongside the usual advice?
- Could my mouthwash be affecting my blood pressure, and is there a non-antibacterial option that still protects my gums?
- I have kidney disease or take other heart medicines: are there reasons beetroot juice might not suit me?
References
- Bryan NS, Bian K, Murad F. Discovery of the nitric oxide signaling pathway and targets for drug development. Front Biosci / The discovery of nitric oxide and its role in vascular biology. 1998 Nobel Prize, Furchgott, Ignarro, Murad. pmc.ncbi.nlm.nih.gov.
- 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(6):818-826. pubmed.ncbi.nlm.nih.gov.
- 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(2):320-327. ahajournals.org.
- 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(3):784-790. ahajournals.org.
- Govoni M, Jansson EA, Weitzberg E, Lundberg JO. The increase in plasma nitrite after a dietary nitrate load is markedly attenuated by an antibacterial mouthwash. Nitric Oxide. 2008;19(4):333-337. pubmed.ncbi.nlm.nih.gov.
- Ras RT, Streppel MT, Draijer R, Zock PL. Flow-mediated dilation and cardiovascular risk prediction: a systematic review with meta-analysis. Int J Cardiol. 2013;168(1):344-351. pubmed.ncbi.nlm.nih.gov.
- Yang YM, Huang A, Kaley G, Sun D. eNOS uncoupling and endothelial dysfunction in aged vessels. Am J Physiol Heart Circ Physiol. 2009;297(5):H1829-H1836. journals.physiology.org.
- Poon ETC, Iu JC, Sum WMK, et al. Dietary Nitrate Supplementation and Exercise Performance: An Umbrella Review of 20 Published Systematic Reviews with Meta-analyses. Sports Med. 2025. pmc.ncbi.nlm.nih.gov.
- Barkhidarian B, Khorshidi M, Shab-Bidar S, Hashemi B. Effects of L-citrulline supplementation on blood pressure: A systematic review and meta-analysis; and related L-citrulline endothelial-function RCTs. Nutr Metab Cardiovasc Dis / Nutrients. ncbi.nlm.nih.gov.
- Campbell A, et al. Effect of continuous aerobic exercise on endothelial function: A systematic review and meta-analysis of randomized controlled trials. Front Physiol. 2023;14:1043108. pmc.ncbi.nlm.nih.gov.
- Srour B, Chazelas E, Deschasaux-Tanguy M, et al. Nitrites and nitrates from food additives and natural sources and cancer risk: results from the NutriNet-Sante cohort. Int J Epidemiol. 2022;51(4):1106-1119. academic.oup.com.
- Food Standards Agency. Nitrates and Nitrites: The Science Explained. food.gov.uk.
This article is educational and does not constitute medical advice, diagnosis, or a treatment recommendation. Medication uses described as “off-label” are not licensed for that purpose in the UK and should only be considered under qualified clinical supervision. Always speak to your GP, pharmacist, or a registered specialist before starting, stopping, or changing any treatment. If you have severe or alarm symptoms - unintentional weight loss, blood in your stool, difficulty swallowing, persistent vomiting, a fever, or severe pain - seek urgent medical care.