In the realm of human physiology and pharmacology, the discovery of nitric oxide (NO) has sparked a wave of groundbreaking research given its remarkable ability to act as a signaling molecule. It plays an important role in various physiological processes in our bodies. However, since it is a naturally occurring gas when it comes to supplementation, it’s not something that’s taken directly in pill form. Instead, one may take its precursors or aim to increase it naturally through different lifestyle choices.
Nitric oxide is a vital signaling molecule in the human body.
Nitric oxide plays multiple roles in promoting vascular health, cellular respiration, and blood clotting regulation.
Supplementation with nitric oxide precursors or donors may have potential benefits for exercise performance and cardiovascular health.
While nitric oxide supplements are generally well-tolerated, potential side effects may occur.
This article discusses the benefits, risks, and natural sources of nitric oxide.
What does nitric oxide do?
The many roles of NO include:
- Promoting vasodilation
- Boosting blood flow
- Aiding mitochondrial respiration
- Regulating platelet function
This elusive molecule continues to be a subject of extensive research, especially due to its potential to improve exercise performance and support heart health. Additionally, research suggests that supplementation with NO precursors may improve their bioavailability and NO synthesis.
It’s been found to promote relaxation of vascular smooth muscle — improving blood flow and augmenting mechanisms contributing to skeletal muscle performance, hypertrophy, and strength adaptations. Nonetheless, more research is warranted to fully understand whether supplementation would be beneficial for individuals.
Understanding the mechanisms
There are two physiological pathways recognized for NO synthesis:
- NO synthase (NOS) dependent. The primary precursor for NOS dependent is the amino acid, L-arginine, which is converted to NO via the action of NOS enzymes. L-citrulline, another amino acid, acts as a secondary NO donor in the NOS-dependent pathway since it can be converted to L-arginine.
- NOS-independent. The NOS-independent pathway relies on dietary nitrate and nitrite, which are found in foods such as spinach, arugula, beets, dairy and meat.
Other molecules, like the dietary supplement glycine propionyl-L-carnitine (GPLC), have been suggested to increase NO levels, although the exact physiological mechanisms remain to be fully understood.
Current research explores the intriguing link between increased NO production and enhanced exercise tolerance and recovery mechanisms. It is suggested that an increase in NO production could enhance oxygen and nutrient delivery to active muscles, thereby improving exercise tolerance and recovery. However, findings from these studies exhibit significant discrepancies.
Benefits of nitric oxide
This single nitrogen and oxygen molecule in our body carries a hefty responsibility. It regulates a multitude of physiological functions that help maintain our bodies' homeostasis and health.
It plays a significant role in relaxing and widening blood vessels, thereby promoting healthy blood flow throughout the body, ensuring all organs receive adequate oxygen and nutrients.
Additionally, NO is involved in the process of cellular respiration in the mitochondria, which is key for the production of ATP, the body's energy currency. NO also impacts blood clotting by regulating platelet function, which can affect wound healing and the risk of excessive bleeding or clot formation.
Nitric oxide and exercise physiology
The potential influence of NO on exercise physiology is a captivating area of research. The hypothesis is that an increase in NO production may enhance oxygen and nutrient delivery to active muscles, and thus boost exercise tolerance and recovery mechanisms.
Several studies utilizing NO donors or precursors have explored this hypothesis in a healthy, trained population. However, the findings have been mixed. While some studies reported benefits in exercise performance following dietary supplementation with NO precursors, others found no such positive effect.
The training status of the subjects seems to be a significant factor influencing the ergogenic effect of NO supplementation. Studies involving untrained or moderately trained healthy subjects showed that NO donors could improve tolerance to aerobic and anaerobic exercise. However, when highly trained subjects were supplemented, no positive effect on performance was observed.
Nitric oxide and cardiovascular health
As a vasodilator, nitric oxide often enters the conversation when it comes to heart health and endothelial function. The endothelial layer, or endothelium, is a single layer of cells that lines the interior surface of blood vessels. It is essential for maintaining vascular homeostasis and ensuring the proper functioning of the cardiovascular system by controlling the release of NO.
It also contributes to maintaining optimal vascular tone and elasticity, which is crucial for normal blood pressure and efficient blood flow. Disruption or dysfunction of the endothelium may lead to a range of cardiovascular diseases, such as atherosclerosis, hypertension, and vascular inflammation.
Studies indicate that dietary nitrate can significantly improve blood vessel function, reduce blood pressure, and enhance exercise performance. Moreover, there is evidence to suggest that nitric oxide donors may benefit individuals with pre-existing cardiovascular conditions. A randomized, double-blind, placebo-controlled trial demonstrated that long-term nitric oxide supplementation improved endothelial function in patients with coronary artery disease.
Nitric oxide and sexual performance
Male sexual performance has been found to be highly dependent on nitric oxide as one of the main vasoactive chemical mediators of erection. When a man becomes sexually aroused, nerve signals stimulate the release of NO in the erectile tissue of the penis. NO then relaxes the smooth muscle cells in the blood vessel walls, causing them to dilate and increase blood flow to the penis. This enhanced blood flow fills the spongy tissues called the corpora cavernosa, resulting in an erection.
Certain pharmaceuticals, like Viagra, employ the nitric oxide pathway to facilitate an increase in blood flow to the penis. This is achieved through the widening of blood vessels, a process known as vasodilation.
However, when NO levels are low, to begin with, or the endothelium is damaged, further reducing NO production, it can lead to erectile dysfunction (ED). Medical conditions including diabetes, hypertension, and atherosclerosis can also damage the endothelium and impair NO release, contributing to ED. A study found that around 52 percent of men experience some form of ED, and there is an increase in incidence from about 5 to 15 percent between ages 40 and 70.
Supplementation with NO donors, such as a high dose of L-arginine (6 g/day), has been found to improve penile erectile function when compared between mild-moderate and severe vasculogenic ED.
Depletion of nitric oxide levels
Several factors can contribute to the depletion of NO levels in the body, including:
- Sedentary lifestyle
- A diet lacking in nitrate rich foods, such as leafy greens, and beets
- A diet lacking in arginine-rich foods, including nuts seafood, and red meat
Certain medications, such as antibiotics, proton pump inhibitors (PPIs), and nonsteroidal anti-inflammatory drugs (NSAIDs), may also adversely affect NO levels.
Boosting nitric oxide levels naturally
Supplementation with NO precursors is not the only way to help boost NO levels in the body. A wide range of healthy lifestyle choices can impact NO production and hence help increase blood flow, reduce blood pressure and enhance endothelial function.
- Consume a diet rich in nitrates, nitrites, and L-arginine. Good sources include leafy green vegetables, beets, nuts, seafood, and red meat.
- Exercise regularly. Both aerobic exercises like running, cycling, or swimming and resistance training can be beneficial for boosting nitric oxide levels.
- Manage stress. Chronic stress can negatively affect endothelial function and nitric oxide production. Engage in stress-reducing activities like meditation, yoga, or spending time in nature.
- Quit smoking. Smoking damages the endothelial cells and reduces NO availability. Quitting smoking can improve endothelial health and increase nitric oxide levels.
- Get adequate sunlight. Exposure to sunlight can stimulate the skin to produce NO.
Nitric oxide risks and side effects
Nitric oxide supplements are generally well-tolerated by most individuals without causing side effects. However, there are cases when one should consider potential risks and side effects. These could include:
- Upset stomach accompanied by pain, bloating, and heartburn
- Irregular heartbeat or palpitations
Additionally, individuals with certain conditions, such as cirrhosis, or liver scarring, guanidinoacetate methyltransferase deficiency, or low blood pressure should abstain from taking NO as it could worsen their symptoms.
Research published in JAMA in 2006 also concluded that individuals should not be provided L-arginine as part of their post-heart attack recovery. It found that it increases the chance of mortality, hospital readmission, or the occurrence of another heart attack. Meanwhile, it did not help improve vascular stiffness measurements or ejection fraction.
Should you supplement with nitric oxide precursors?
Many of our body's physiological processes that contribute to health, longevity, and performance enhancement rely on nitric oxide. Whether through diet, exercise, or supplementation, optimizing NO levels may offer benefits. However, the decision to supplement should not be made lightly.
Be aware of potential side effects and be sure to consult with a healthcare provider prior to supplementing with NO whether it’s to improve athletic performance, sexual performance, or overall cardiovascular health.
Most studies on NO supplementation have primarily focused on young male populations. Further research is needed to explore the effects of NO supplements in elderly and female populations, particularly as NO metabolism may be affected by age and estrogen status.
Moreover, possible side effects and interactions should be considered. It's also important to remember that while dietary supplements can complement a healthy lifestyle, they should not replace a balanced diet and regular physical activity.
How many grams of L-arginine should I take?
It depends on what you are taking it for. According to the Cleveland Clinic, the average dosage of L-arginine is between 6 g to 30 g per day. Take no more than 6 g at once as it can cause gastrointestinal distress in higher doses. If taken prior to a workout, aim for between 3 g to 6 g.
Should I take both L-arginine and L-citrulline?
Research has found that taking both L-arginine and L-citrulline prior to exercise increased NO levels as well as the perception of physical exertion. Additionally, another study on animal models concluded that supplementation with both lead to a significantly greater increase in plasma NO levels.
What dosage of L-arginine and L-citrulline is best?
Aim for 1 g of each as it’s been found to increase plasma L-arginine levels effectively in humans, which then increased NO levels respectively.
- Nutrients. Supplementation with nitric oxide precursors for strength performance: a review of the current literature.
- The American Journal of Sports Medicine. The effect of nitric-oxide-related supplements on human performance.
- Circulation. Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans.
- Journal of Endocrinological Investigation. Long-term high-dose L-arginine supplementation in patients with vasculogenic erectile dysfunction: a multicentre, double-blind, randomized, placebo-controlled clinical trial.
- JAMA. L-arginine therapy in acute myocardial infarction: the vascular interaction with age in myocardial infarction (VINTAGE MI) randomized clinical trial.
Show all references
- Cleveland Clinic. L-Arginine.
- European Journal of Applied Physiology. A combination of oral l-citrulline and l-arginine improved 10-min full-power cycling test performance in male collegiate soccer players: a randomized crossover trial.
- Biochemical and Biophysical Research Communications. Oral supplementation with a combination of l-citrulline and l-arginine rapidly increases plasma l-arginine concentration and enhances NO bioavailability.
- Bioscience, Biotechnology, and Biochemistry. The effects on plasma L-arginine levels of combined oral L-citrulline and L-arginine supplementation in healthy males.