NITRIC OXIDE

QUICK TAKES

🚀 Exercise Performance Boost: Just two cups of beetroot juice daily for 6 days can extend your exercise time to exhaustion by roughly 20%, while a single dose can improve power output by 5% (Bailey et al., 2010).

⚠️ The Antioxidant Connection: Taking arginine or other NO boosters without adequate antioxidant support may backfire, potentially increasing mortality by creating harmful peroxynitrite instead of beneficial nitric oxide.

💊 Mouthwash Sabotages Benefits: Using antiseptic mouthwash or taking antibiotics impair the conversion of dietary nitrates to beneficial nitrites, blocking nitric oxide production from food sources.

🍃 Raw leafy greens, especially arugula and lettuce offer the largest amount of nitrates. Up to 6 cups per day may be a good goal for overachievers who want to optimize cardiovascular and overall health.

🏔️ Altitude Creates a Paradox: While nitric oxide normally helps with oxygen delivery, reducing NO synthesis at high altitude may actually be protective by preventing dangerous lung fluid leakage and conserving precious oxygen (Hennis et al., 2022).

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Beet chews instead of beet juice: The company HumanN has been developing these supplements, some of which have recently received Certified for Sport® certification (meaning that they do not contain unsafe levels of contaminants, prohibited substances or masking agents, and that what is on the label matches what is in the product). I’m curious about these and hope to soon provide access to these for patients.

Arugula: the single most useful high nitrate vegetable; others include rhubarb (low sugar recipe follows), butter leaf lettuce, baby kale, chard, and beet greens, mesclun mix, oak leaf lettuce, and bok choi. Many other vegetables have highly variable amounts depending on cultivation.

RECIPE: SOFTLY STEWED VANILLA GINGER RHUBARB (from Swoon Food, click for link).

Beet kvass: 2 cups of beet juice are needed for exercise improvements; beet kvass may be a better choice as some of the sugars would have been used up by the bacteria, and it would provide probiotic bacteria along with the nitrates.

Neo-40 and Vascanox, stretching and isometric exercise (especially of large muscles) provide nitric oxide, or raise nitric oxide availability and reduce blood pressure. As explained in the Deep Dive, these are always best used in the context of reducing oxidative stress, preferably via a diet high in antioxidants.

DEEP DIVE: What You Need to Know About Nitric Oxide

What is Nitric Oxide and Why Does It Matter?

Nitric oxide (NO) is a gaseous molecule that serves as one of the body's most important signaling compounds. It enhances bodily function through dilating blood vessels for improved circulation, and through its effects on mitochondrial number and function (Dinetz et al., 2024).

The significance of NO becomes apparent when we consider that endogenous NO production significantly decreases by age 40, contributing to cardiovascular aging and disease progression (Dinetz et al., 2024). This age-related decline makes understanding NO production and supplementation increasingly relevant for healthy aging.

How the Body Produces Nitric Oxide

The body generates NO through two distinct pathways, each contributing different amounts to total production.

The Primary Pathway: Blood Vessel (Endothelial) Production (70%)

The majority of NO comes from the action of endothelial nitric oxide synthase (eNOS), which converts the amino acid arginine to citrulline in blood vessels, releasing NO in the process. This enzymatic reaction requires oxygen and several vitamin cofactors, including riboflavin (providing FAD and FMN), niacin (NADP), calcium-calmodulin, iron, heme, glutathione, and tetrahydrobiopterin (BH4). The nervous system uses a related enzyme called neuronal NOS, while immune cells utilize inducible NOS.

The Dietary Pathway: Nitrate-Nitrite-NO Conversion (30%)

The remaining NO comes from consuming nitrate-rich foods. Bacteria living on the tongue convert dietary nitrates to nitrites, which are then swallowed and converted to NO by gastric acid. This pathway becomes increasingly important as eNOS function declines with age.

The Exercise Connection

Physical activity provides a natural boost to NO production through shear stress on blood vessels, which stimulates eNOS activity. This fits with the profound effect regular exercise exerts on so many aspects of health.

Just stretching also increases NO production (Hotta et al., 2022). Isometric exercise (especially using large muscles) has a similar effect (Ohler et al., 2020).

Supplementation studies consistently demonstrate exercise benefits. Taking L-arginine and L-citrulline enhances exercise endurance and reduces perceived effort, particularly in moderately trained or untrained individuals (Kiani et al., 2022). Beetroot juice supplementation (2 cups of it), providing 434mg of sodium nitrate daily for six days, extends exhaustion time by approximately 20% and improves power output by 5% with just a single dose (Bailey et al., 2010).

The Critical Role of Antioxidants

Perhaps the most important aspect of NO supplementation is the absolute requirement for adequate antioxidant support. Without proper antioxidant nutrition, NO can be oxidized into peroxynitrite, a harmful compound that causes excessive oxidative stress and end-organ dysfunction. This may explain why some studies using chronic L-arginine supplementation found likely increased mortality.

As we age, several factors impair NO production beyond simple enzyme decline. There's decreased NOS enzyme expression and increased arginase activity (which interferes with eNOS function), both driven by oxidative stress and oxidation of BH4, causing "NOS uncoupling" (Taddei et al., 2001). In this context, L-arginine supplementation becomes ineffective, even harmful, and antioxidant supplementation becomes the better approach.

Dietary Sources and Practical Considerations

High-nitrate foods include arugula, spinach, beets, kale, and other green leafy vegetables. However, getting physiologically noticeable doses through diet presents significant challenges. Research analyzing vegetables from five US cities revealed more than tenfold differences in nitrate content of the same vegetable across locations, and similar variations between different vegetables (Hord et al., 2009).

This means dietary recommendations must account for significant geographical and agricultural variations. Aiming for 6 cups of raw vegetables daily should cover these needs, but entails a diet change for many people.

For the dietary pathway to work effectively, several conditions must be met: adequate nitrate-reducing oral bacteria, sufficient gastric acid production, and avoidance of interference factors like antiseptic mouthwash or antibiotics.

Adequate sleep and sleep recovery are linked to increased NO production, particularly in the brain. During sleep deprivation, NO generation rises in the basal forebrain, aiding the induction of recovery sleep. Pharmacological inhibition of NO synthesis can prevent recovery sleep, indicating that NO is necessary for normal sleep homeostasis (Kalinchuk et al., 2006).

Paced, slow, or nasal breathing increases NO levels. NO is produced in the nasal sinuses and delivered to the lungs during nasal breathing, resulting in higher pulmonary oxygenation and vascular relaxation compared to oral breathing. Deep or slow breathing and nasal breathing stimulate endogenous NO production, improving blood flow and potentially reducing blood pressure (Harbour et al., 2022).

Fasting and time-restricted eating also likely improve NO production (Balasubramanian et al., 2020).

Clinical Applications and Cardiovascular Benefits

Apart from focusing on food sources and health practices, it is possible to take NO supplements. NO supplementation demonstrates significant cardiovascular benefits in clinical studies. In patients with prehypertension, NO supplementation (specifically with Neo-40 Professional) significantly decreased resting blood pressure from 138/84 mmHg to 126/78 mmHg and increased six-minute walk test distance from 596 to 650 meters (Biswas et al., 2015). Patients also showed improvements in both physical and mental component summary scores on quality of life assessments.

A study using the Neo-40 tablets (15-20mg of supplemental sodium nitrite) found significant reductions in triglycerides and blood pressure in patients over 40 (Zand et al., 2011). Most remarkably, in subjects with stable carotid plaque, NO supplementation led to an 11% reduction in carotid plaque after six months (Lee, 2016). This sort of result is so puzzling: why have we not heard more about this? Why isn’t everyone on Neo-40? What are we missing? Nitric oxide (NO) is widely recognized as a central protective molecule in the prevention of atherosclerotic plaque accumulation. It works through several different pathways to maintain blood vessel health and prevent coronary artery disease.

Special Populations and Considerations

👍️ Pregnancy: Arginine supplementation with antioxidant vitamins may prevent pre-eclampsia in high-risk populations (Vadillo-Ortega et al., 2011).

🙅 Liver Disease: Nitric oxide supplementation could worsen liver function in individuals with cirrhosis due to excessive oxidative stress in that setting (Gracia-Sancho et al., 2008).

🤷 High Altitude?: The relationship between NO and altitude creates an interesting paradox. While NO normally improves oxygen delivery, reducing NO synthesis at high altitude may be protective by preventing excessive vasodilation and capillary leakage that could contribute to high altitude pulmonary edema. Reduced NO production may also conserve oxygen for essential cellular processes rather than the oxygen-dependent NO synthesis reaction, and limit formation of harmful peroxynitrite under hypoxic stress (Hennis et al., 2022). It is probably optimal to focus on antioxidant fruits and vegetables, nuts and seeds, and antioxidant supplements which have some demonstrated effectiveness in preventing acute mountain sickness, rather than on NO supplementation.

Emerging Supplements and Future Directions

Glycine propionyl-L-carnitine (GPLC) represents a promising approach, improving NO metabolism through antioxidant properties and potential eNOS gene expression enhancement. A single 4.5g dose taken 90 minutes before exercise significantly increased peak power by 5.2% and decreased power decrement by 5.2% (Jacobs et al., 2009). However, research remains limited 15 years after initial studies, suggesting that additional studies were not as successful.

Other nutraceuticals showing promise include resveratrol, which improves lipid profiles and increases endothelial NOS, and curcumin, which exhibits strong anti-inflammatory effects and activates longevity genes (Dinetz et al., 2024).

Practical Recommendations

Based on current evidence, effective NO support requires a comprehensive approach:

1. Prioritize antioxidant support before considering NO precursors

2. Choose dietary sources carefully, understanding geographical and growing method variations

3. Maintain oral and gastric health for optimal nitrate-nitrite conversion

4. Consider timing and dosing - bolus dosing appears more effective than divided doses

5. Monitor for contraindications in liver disease or specific altitude exposures

The future of nitric oxide research appears particularly promising in cardiovascular medicine, with potential applications ranging from post-myocardial infarction treatment to comprehensive anti-aging protocols.

REFERENCES

Bailey, S. J., Fulford, J., Vanhatalo, A., Winyard, P. G., Blackwell, J. R., DiMenna, F. J., Wilkerson, D. P., Benjamin, N., & Jones, A. M. (2010). Dietary nitrate supplementation enhances muscle contractile efficiency during knee-extensor exercise in humans. Journal of Applied Physiology.

Balasubramanian P, DelFavero J, Ungvari A, Papp M, Tarantini A, Price N, de Cabo R, Tarantini S. Time-restricted feeding (TRF) for prevention of age-related vascular cognitive impairment and dementia. Ageing Res Rev. 2020

Bescós, R., Sureda, A., Tur, J. A., & Pons, A. (2012). The effect of nitric-oxide-related supplements on human performance. Sports Medicine.

Biswas, O. S., Gonzalez, V. R., & Schwarz, E. R. (2015). Effects of an oral nitric oxide supplement on functional capacity and blood pressure in adults with prehypertension. Journal of Cardiovascular Pharmacology and Therapeutics.

Dinetz, E., Zeballos-Palacios, C., & Martinez, C. A. (2024). Addressing the Missing Links in Cardiovascular Aging. Clinical Interventions in Aging. Erratum in: Clinical Interventions in Aging, 2024.

Gracia-Sancho, J., Lavina, B., Rodriguez-Vilarrupla, A., Garcia-Caldero, H., Fernandez, M., Bosch, J., & Garcia-Pagan, J. C. (2008). Increased oxidative stress in cirrhotic rat livers: A potential mechanism contributing to reduced nitric oxide bioavailability. Hepatology.

Harbour E, Stöggl T, Schwameder H, Finkenzeller T. Breath Tools: A Synthesis of Evidence-Based Breathing Strategies to Enhance Human Running. Front Physiol. 2022

Hennis, P. J., Cumpstey, A. F., O'Doherty, A. F., Fernandez, B. O., Gilbert-Kawai, E. T., Mitchell, K., Moyses, H., Cobb, A., Meale, P., Pöhnl, H., Mythen, M. G., Grocott, M. P. W., Levett, D. Z. H., Martin, D. S., & Feelisch, M. (2022). Dietary Nitrate Supplementation Does Not Alter Exercise Efficiency at High Altitude - Further Results From the Xtreme Alps Study. Frontiers in Physiology.

Hord, N. G., Tang, Y., & Bryan, N. S. (2009). Food sources of nitrates and nitrites: the physiologic context for potential health benefits. American Journal of Clinical Nutrition.

Hotta K, Muller-Delp J. Microvascular Adaptations to Muscle Stretch: Findings From Animals and the Elderly. Front Physiol. 2022

Houston, M., & Hays, L. (2014). Acute effects of an oral nitric oxide supplement on blood pressure, endothelial function, and vascular compliance in hypertensive patients. Journal of Clinical Hypertension (Greenwich).

Islam, M. N., Rauf, A., Fahad, F. I., Emran, T. B., Mitra, S., Olatunde, A., Shariati, M. A., Rebezov, M., Rengasamy, K. R. R., & Mubarak, M. S. (2022). Superoxide dismutase: an updated review on its health benefits and industrial applications. Critical Reviews in Food Science and Nutrition.

Jacob, J., Gopi, S., & Divya, C. (2017). A Randomized Single Dose Parallel Study on Enhancement of Nitric Oxide in Serum and Saliva with the Use of Natural Sports Supplement in Healthy Adults. Journal of Dietary Supplements.

Jacobs, P. L., Goldstein, E. R., Blackburn, W., Orem, I., & Hughes, J. J. (2009). Glycine propionyl-L-carnitine produces enhanced anaerobic work capacity with reduced lactate accumulation in resistance trained males. Journal of the International Society of Sports Nutrition.

Kalinchuk AV, Stenberg D, Rosenberg PA, Porkka-Heiskanen T. Inducible and neuronal nitric oxide synthases (NOS) have complementary roles in recovery sleep induction. Eur J Neurosci. 2006

Kiani, A. K., Bonetti, G., Medori, M. C., Caruso, P., Manganotti, P., Fioretti, F., Nodari, S., Connelly, S. T., & Bertelli, M. (2022). Dietary supplements for improving nitric-oxide synthesis. Journal of Preventive Medicine and Hygiene.

Lee, E. (2016). Effects of nitric oxide on carotid intima media thickness: a pilot study. Alternative Therapies in Health and Medicine.

Olher RR, Rosa TS, Souza LHR, Oliveira JF, Soares BRA, Ribeiro TBA, Souza IRC, Neves RVP, Sousa CV, Deus LA, Marchetti PH, Simoes HG, Moraes MR. Isometric Exercise with Large Muscle Mass Improves Redox Balance and Blood Pressure in Hypertensive Adults. Med Sci Sports Exerc. 2020.

Ramos-Jiménez, A., Hernández-Torres, R. P., Hernández-Ontiveros, D. A., Ortiz-Ortiz, M., López-Fregoso, R. J., Martínez-Sanz, J. M., Rodríguez-Uribe, G., & Hernández-Lepe, M. A. (2024). An Update of the Promise of Glycine Supplementation for Enhancing Physical Performance and Recovery. Sports (Basel).

Taddei, S., Virdis, A., Ghiadoni, L., Salvetti, G., Bernini, G., Magagna, A., et al. (2001). Age-related reduction of NO availability and oxidative stress in humans. Hypertension.

Vadillo-Ortega, F., Perichart-Perera, O., Espino, S., Avila-Vergara, M. A., Ibarra, I., Ahued, R., Godines, M., Parry, S., Macones, G., & Strauss, J. F. (2011). Effect of supplementation during pregnancy with L-arginine and antioxidant vitamins in medical food on pre-eclampsia in high risk population: randomised controlled trial. BMJ.

Zand, J., Lanza, F., Garg, H. K., & Bryan, N. S. (2011). All-natural nitrite and nitrate containing dietary supplement promotes nitric oxide production and reduces triglycerides in humans. Nutrition Research