Scientific Research On Nitric Oxide and Athletic Performance


Scientific Research On Nitric Oxide and Athletic Performance

Ever since the 1998 Nobel Prize in Medicine was awarded to 3 American researcher for their discovery on how your endothelium (which lines all of your cardiovascular system) converts the semi-essential amino acid L-arginine into nitric oxide, there has been an explosion of research in this area.


Most of this research has focused on how nitric oxide helps to regulate cardiovascular health and function. It’s been clearly established that nitric oxide plays a critical role in vasodilatation, blood flow, mitochondrial respiration, and platelet function. There is a growing body of scientific studies on humans that are now beginning to confirm what has been seen in animal studies:


That therapeutic levels of nitric oxide can initiate reparative mechanism to heal damage

done to the endothelium to help reverse plaque formations and calcification.

This returns more of the surface volume of the endothelium back to

a healthy, functioning tissue.


Nitric OxideThe resulting benefit is increased nitric oxide levels that approach those seen in younger age categories. This helps to reduce cardiovascular risk factors and provides a natural preventative process to lowering those illnesses that are associated with cardiovascular disease like high blood pressure, strokes, and heart attacks.


Some of this research has centered on nitric oxide and athletic performance. Can nitric oxide improve your circulation to allow for greater deliver of oxygen and nutrients and proper removal of waste products like lactic acid? Will this result in improved workout capacity and athletic performance? Does this result in less lactic acid production because you’re able to work at higher aerobic capacities?


The following studies will give you a fair perspective on this limited, but growing body of research. You’ll find studies showing clear benefits. You’ll find studies showing conflicting results to no benefits. Like all studies they measure different parameters and then make their conclusions based on those parameters. Often these studies use only single ingredients like L-arginine only. Then the question is how much and what is the quality of the L-arginine use. Sometimes these studies only test a short window of time to see if a benefit has been gained.

Here are my observations about these studies and my experience in working with nitric oxide therapy for improved human performance:


  1. The purity and potency of the L-arginine is absolutely critical to the outcome. Many studies use synthetic formulations with carrier molecules to enhance absorption. Naturally derived L-arginine is always the best.

  2. When studies use only L-arginine they don’t understand the metabolic process and how this affects long term benefits. L-arginine by itself only provides a short window of increased nitric oxide production with no long term therapeutic benefit. It must be combined with other ingredients to enhance the ability of the endothelium to maximize its production of nitric oxide over a long period of time. It would be like using only water to hydrate yourself without eating any food. Water is good but you need nutrients to properly fuel your body for optimal performance.

  3. The following key nutrients will help provide the greatest opportunity for improved nitric oxide production:

    L-arginine and L-citrulline – L-arginine is the main source that the eNOS enzymes will use to create nitric oxide. L-citrulline can then convert the metabolic molecules spun off during the creation of nitric oxide to reform L-arginine to continue to fuel the eNOS enzymes for greater and more efficient production of nitric oxide.

    Vitamins D3 and K2 – These vitamins (although vitamin D3 is now considered a hormone) help to properly regulate calcium levels in the blood stream. This is important because the eNOS enzymes used for the creation of nitric oxide are calcium dependent.

    Pomegranate fruit concentrate – This nutritional ingredient has been clearly shown in multiple studies to enhance the enzymatic activity of the eNOS enzymes for improved nitric oxide production.

  4. Improvements in the function of the endothelium don’t just happen overnight. They happen over time. So short term studies using one dose may see a benefit in improved blood flow. However, they may not see an improvement in muscular endurance because the body hasn’t adjusted to more efficient methods for the uptake of oxygen and nutrients and the elimination of waste products. It would be like trying to retool a car factory in an hour to produce a new car design.

  5. Your endothelium is being damaged all the time. This damage accumulates over time. As Nitric Oxide Production as We Age this damage occurs it lessen the productivity of the endothelium. The older you are the more accumulative damage since most people do not actively nourish their endothelium with the ingredients it needs for optimal health and function. As you begin this process of specifically nourishing the endothelium to produce therapeutic levels of nitric oxide, you can then initiate the ability of nitric oxide to begin the reparative process of healing damage done to the endothelium. Over time this process returns more and more surface volume back into play allowing for more and more production of nitric oxide and the benefits this can provide for human performance.

With these observations in mind, here are some of the better studies done in the area of nitric oxide and athletic performance. Studies that show benefits as well as studies that show no benefits.  To connect to the original material, just click on the title of the study and a new window will open providing you with the original source material.


The Effect of Nitric Oxide on Exercise Performance and Respiration Recovery Time

Authors: Brian Lee and Nathania Nguyen Mentor: Dr. Maureen Knabb


A blind study was conducted to see the effects that the nitric oxide (NO) supplement, “MRI Nitric Oxide Platinum Hemodilator,” has on exercise performance and respiration recovery time. Nitric oxide causes vasodilation of the blood vessel and a subsequent increase in blood flow to skeletal muscles to ensure an adequate supply of oxygen and metabolic fuel, as well as the removal of metabolic waste. The experiment was conducted over two separate days on four different individuals (two males and two females). On the first day, baseline data was collected before and after exercise. On the second day, two of the individuals (one male and one female) received the NO supplement and the other two individuals (one male and one female) received a corn starch placebo; just as the first day, data was collected before and after exercise. Data included results for blood pressure, respiration recovery time and muscle fatigue. Blood pressure decreased prior to exercise for those who received the supplement and stayed the same for those who did not receive the supplement. Respiration recovery time also decreased for those who received the supplement. Those who did not receive the supplement had a higher respiration recovery time, or the same recovery time. Evidently, anecdotal evidence supporting the effects of NO supplements on athletic performance may be due to its respiratory effects rather than its intended muscular effects. The results of this study indicated a contradiction with nitric oxide’s advertised physiological effects.


The Effect of Nitric-Oxide-Related Supplements on Human Performance

Bescós R1, Sureda A, Tur JA, Pons A.

Author information

  • 1National Institute of Physical Education INEFC-Barcelona, Physiology Laboratory, University of Barcelona, Barcelona, Spain.


Nitric oxide (NO) has led a revolution in physiology and pharmacology research during the last two decades. This labile molecule plays an important role in many functions in the body regulating vasodilatation, blood flow, mitochondrial respiration and platelet function. Currently, it is known that NO synthesis occurs via at least two physiological pathways: NO synthase (NOS) dependent and NOS independent. In the former, L-arginine is the main precursor. It is widely recognized that this amino acid is oxidized to NO by the action of the NOS enzymes. Additionally, L-citrulline has been indicated to be a secondary NO donor in the NOS-dependent pathway, since it can be converted to L-arginine. Nitrate and nitrite are the main substrates to produce NO via the NOS-independent pathway. These anions can be reduced in vivo to NO and other bioactive nitrogen oxides. Other molecules, such as the dietary supplement glycine propionyl-L-carnitine (GPLC), have also been suggested to increase levels of NO, although the physiological mechanisms remain to be elucidated. The interest in all these molecules has increased in many fields of research. In relation with exercise physiology, it has been suggested that an increase in NO production may enhance oxygen and nutrient delivery to active muscles, thus improving tolerance to physical exercise and recovery mechanisms. Several studies using NO donors have assessed this hypothesis in a healthy, trained population. However, the conclusions from these studies showed several discrepancies. While some reported that dietary supplementation with NO donors induced benefits in exercise performance, others did not find any positive effect. In this regard, training status of the subjects seems to be an important factor linked to 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 indicated. In addition, all this evidence is mainly based on a young male population. Further research in elderly and female subjects is needed to determine whether NO supplements can induce benefit in exercise capacity when the NO metabolism is impaired by age and/or estrogen status.


Bolus Arginine Supplementation Affects Neither Muscle Blood Flow nor Muscle Protein Synthesis in Young Men at Rest or After Resistance Exercise1,2,3

  1. Jason E. Tang4,

  2. Paul J. Lysecki4,

  3. Joshua J. Manolakos4,

  4. Maureen J. MacDonald4,

  5. Mark A. Tarnopolsky5, and

  6. Stuart M. Phillips4,*

+ Author Affiliations

  1. 4Department of Kinesiology, Exercise Metabolism Research Group and
  2. 5Departments of Pediatrics and Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada


The aim of this study was to investigate the ergogenic potential of arginine on NO synthesis, muscle blood flow, and skeletal muscle protein synthesis (MPS). Eight healthy young men (22.1 ± 2.6 y, 1.79 ± 0.06 m, 76.6 ± 6.2 kg; mean ± SD) participated in 2 trials where they performed a bout of unilateral leg resistance exercise and ingested a drink containing either 10 g essential amino acids with 10 g l-arginine (ARG) or an isonitrogenous control (CON). Femoral artery blood flow of both the nonexercised and exercised leg was measured continuously using pulsed-wave Doppler ultrasound, while rates of mixed and myofibrillar MPS were determined using a primed continuous infusion of l-[ring-13C6] or l-[ring-2H5]phenylalanine. The plasma arginine concentration increased 300% during the ARG trial but not during the CON trial (P < 0.001). Plasma nitrate, nitrite, and endothelin-1, all markers of NO synthesis, did not change during either the ARG or CON trial. Plasma growth hormone increased to a greater degree after exercise in the ARG trial than CON trial (P < 0.05). Femoral artery blood flow increased 270% above basal in the exercised leg (P < 0.001) but not in the nonexercised leg, with no differences between the ARG and CON trials. Mixed and myofibrillar MPS were both greater in the exercised leg compared with the nonexercised leg (P < 0.001), but did not differ between the ARG and CON treatments. We conclude that an oral bolus (10 g) of arginine does not increase NO synthesis or muscle blood flow. Furthermore, arginine does not enhance mixed or myofibrillar MPS either at rest or after resistance exercise beyond that achieved by feeding alone.


No Effect of Short-Term Arginine Supplementation on Nitric Oxide Production, Metabolism and Performance in Intermittent Exercise in Athletes

Liu TH1, Wu CL, Chiang CW, Lo YW, Tseng HF, Chang CK.

Author information

  • 1Department of Physical Education, Taiwan Sport University, 404 Taichung, Taiwan.


Arginine supplementation has been shown to alleviate endothelial dysfunction and improve exercise performance through increasing nitric oxide production in patients with cardiopulmonary diseases. In addition, arginine supplementation could decrease accumulations of lactate and ammonia, metabolites involved in development of muscular fatigue. The aim of this study was to investigate the effect of short-term arginine supplementation on performance in intermittent anaerobic exercise and the underlying mechanism in well-trained male athletes. Ten elite male college judo athletes participated with a randomized crossover, placebo-controlled design. The subjects consumed 6 g/day arginine (ARG trial) or placebo (CON trial) for 3 days then performed an intermittent anaerobic exercise test on a cycle ergometer. Blood samples were collected before supplementation, before and during exercise and 0, 3, 6, 10, 30 and 60 min after exercise. ARG trial had significantly higher arginine concentrations than CON trial at the same time point before, during and after exercise. In both trials, nitrate and nitrite concentration was significantly higher during and 6 min after exercise comparing to the basal concentration. The increase in nitrate and nitrite concentration during exercise in both trials was parallel to the increase in plasma citrulline concentrations. There was no significant difference between the 2 trials in plasma nitrate and nitrite, lactate and ammonia concentrations and peak and average power in the exercise. The results of this study suggested that short-term arginine supplementation had no effect on nitric oxide production, lactate and ammonia metabolism and performance in intermittent anaerobic exercise in well-trained male athletes.


The Bradykinin β2 Receptor (BDKRB2) and Endothelial Nitric Oxide Synthase 3 (NOS3) Genes and Endurance Performance During Ironman Triathlons

  1. Colleen J. Saunders2,

  2. Stavroulla L. Xenophontos3,

  3. Marios A. Cariolou3,

  4. Lakis C. Anastassiades4,

  5. Timothy D. Noakes2 and

  6. Malcolm Collins1,2,*

+ Author Affiliations

  1. 1MRC/UCT Research Unit for Exercise Science and Sports Medicine of the Medical Research Council of South Africa and
  2. 2Department of Human Biology, University of Cape Town, South Africa,
  3. 3Molecular Genetics Department B, Laboratory of Forensic Genetics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus and
  4. 4Cardiovascular Diagnostic Centre, Nicosia, Cyprus


We have previously shown that the insertion allele of the angiotensin-converting enzyme (ACE) gene was over-represented in the fastest South-African-born finishers of the South African Ironman Triathlons. As ACE is a component of the skeletal muscle kallikrein-kinin system (KKS), the aim of this study is to determine if there are any further associations between polymorphisms within the BDKRB2 and NOS3 genes, which encode for the KKS components, bradykinin β2 receptor and nitric oxide synthase, respectively, and ultra-endurance performance during the Ironman Triathlons. Four-hundred and forty-three male Caucasian triathletes who completed the 2000 and/or 2001 South African Ironman Triathlons and 203 healthy Caucasian male control subjects were genotyped for the functional −9/+9 polymorphism within exon 1 of the BDKRB2 gene and the G894T NOS3 gene polymorphisms. The BDKRB2 −9/−9 genotype occurred at a significantly higher frequency when the triathlete group (27.0%) was compared with the control group (19.3%, P=0.035). When divided into tertiles, there was also a significant linear trend for the NOS3 GG genotype distribution among the fastest (35.0%), middle (40.4%) and slowest (46.9%) finishers (P=0.039). The overall finishing times of the triathletes with an NOS3 GG genotype together with a BDKRB2 +9 allele were significantly slower than those with other genotype combinations (P=0.001). The NOS3/BDKRB2 genotype (β=−0.150, B=−31.48, P=0.002), together with body mass index and age, accounted for 14.6% of the variance in the overall race time for the triathlon. In conclusion, both the NOS3 and BDKRB2 genes are associated with the actual performance during the Ironman Triathlons.


Nitric Oxide Production and NO Synthase Gene Expression Contribute to Vascular Regulation During Exercise

Authors: Shen W, Zhang X, Zhao G, Wolin MS, Sessa W, Hintze TH


Nitric oxide (NO) is a vasodilator produced under normal physiologic conditions primarily by the vascular endothelium lining all blood vessels. The primary stimulus for the production of nitric oxide by the constitutive endothelial nitric oxide synthase (ECNOS, Type II) found in blood vessels is most likely the shear stress, the frictional force, caused by blood flowing through blood vessels. During exercise there is an increase in cardiac output and redistribution of blood flow to increase blood flow in skeletal muscle and in the coronary circulation. These adjustments provide increased oxygen delivery to support aerobic energy production and to sustain the exercise response. NO may be involved in the regulation of vascular tone in exercising skeletal and cardiac muscle by promoting, enhancing the metabolic vasodilation. In addition, the production of NO by capillary endothelium may regulate oxygen consumption by mitochondria through chemical interactions between NO and the iron-sulfur center of these enzymes. Finally, brief exercise training may alter the gene expression for the enzyme, the constitutive endothelial NO synthase, which forms NO and may be part of the vascular adaptation seen after aerobic exercise training. Furthermore, if there is a genetic predisposition to produce NO, as in world class athletes or animals bred to race, NO may contribute to spectacular exercise performance. These three potential roles of NO will be discussed and data presented to support each of these in our review.


Acute L-arginine Supplementation Reduces the O2 Cost of Moderate-Intensity Exercise and Enhances High-Intensity Exercise Tolerance

Stephen J. Bailey , Paul G. Winyard , Anni Vanhatalo , Jamie R. Blackwell , Fred J. DiMenna , Daryl Paul Wilkerson , Andrew M. Jones


It has recently been reported that dietary nitrate supplementation which increases plasma nitrite concentration, a biomarker of nitric oxide (NO) availability, improves exercise efficiency and exercise tolerance in healthy humans. We hypothesised that dietary supplementation with L-arginine, the substrate for nitric oxide synthase (NOS), would elicit similar responses. In a double-blind, crossover study, nine healthy males (aged 19-38 years) consumed a 500 mL beverage containing 6 g of L-arginine (ARG) or a placebo beverage (PLA), and completed a series of ‘step’ moderate-intensity and severe-intensity exercise bouts 1 h post-ingestion. Plasma [nitrite] was significantly greater following L-arginine consumption compared to placebo (ARG: 331 ± 198 vs. PLA: 159 ± 102 nM; P<0.05) and systolic blood pressure was significantly reduced (ARG: 123 ± 3 vs. PLA: 131 ± 5 mmHg; P<0.01). The steady-state VO2 during moderate-intensity exercise was reduced by 7% in the ARG condition (ARG: 1.48 ± 0.12 vs. PLA: 1.59 ± 0.14 L•min-1; P<0.05). During severe-intensity exercise, the VO2 slow component amplitude was reduced (ARG: 0.58 ± 0.23 vs. PLA: 0.76 ± 0.29 L•min-1; P<0.05) and the time-to-exhaustion was extended (ARG: 707 ± 232 s vs. PLA: 562 ± 145 s; P<0.05) following ARG. In conclusion, similar to the effects of increased dietary nitrate intake, elevating NO bioavailability through dietary L-arginine supplementation reduced the O2 cost of moderate-intensity exercise and blunted the VO2 slow component and extended the time-to-exhaustion during severe-intensity exercise.


Can Arginine Boost Endurance? A new study reverses earlier findings.


Alex Hutchinson


March 9, 2013

Positive study results are more interesting than negative ones. This is no great secret – in fact, it’s a serious and widely acknowleged problem in health research and journalism. If you do 10 studies of some miracle cure, and nine of them find that it doesn’t work but one of them produces seemingly hopeful results, guess which one is going to get accepted in a big journal and picked up by the media? I mention this because I was just flipping through new studies in the European Journal of Applied Physiology, and noticed one called “No effect of acute L-arginine on O(2) cost or exercise tolerance.” Precisely the kind of non-result that none of us really need to know about, so I was about to keep scanning…

But I paused over this one, because it just so happens that a few years ago I wrote with great enthusiasm about a study titled “Acute L-arginine supplementation reduces the O2 cost of moderate-intensity exercise and enhances high-intensity exercise tolerance” – exactly the opposite of the new result. Huh? Deepening the mystery, it turns out that both studies were performed by (mostly) the same group of researchers, in Andy Jones’s lab at Exeter University. So why the contradictory results?

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