Athletes are constantly searching for methods to become leaner, more muscular, faster, stronger, and more explosive. An educated trainee understands clearly that the majority of their success related to these goals is primarily attributed to well-designed and executed exercise training sessions, in addition to optimal nutritional intake (including whole food and perhaps meal replacement shakes and bars). Such considerations, coupled with adequate sleep and other lifestyle approaches aimed at optimal recovery, could be theorized to account for 90 to 95% of a trainee's ultimate success in reaching their genetic ceiling for aesthetics and performance. Dietary supplements may contribute slightly beyond this point.
Unfortunately, one trip through the typical bodybuilding/fitness magazine (i.e., advertisement collection), and you may be lead to believe that you will never reach these goals unless you are using the newest dietary supplement. While some supplements indeed have efficacy and have been shown in peer-reviewed clinical trials to provide significant benefits over placebo, this is certainly not the norm. More often than not, sport supplement companies rely on “borrowed research” and paid endorsements from some of the top athletes in the industry to market and sell their products. Unlike pharmaceuticals where companies spend years of effort and millions of dollars on research and development, and then maybe a product makes it to the market, this is not the path for dietary supplements. Rather, the company brings the product to the market first, aggressively hypes it up, and then maybe the research follows.
A careful examination of many dietary supplements currently being sold indicates that many of these products have absolutely no efficacy in human subjects, nor would they be expected to based on the relevant biochemistry of the included ingredients. This is especially true when considering the often extremely low dosages of said “key” ingredients. As always, buyer beware. Or more specifically, individuals should do their own investigating and come to their own educated decision regarding the product's potential effectiveness. This is easily done by searching for relevant scientific studies using a medical database such as PubMed (www.pubmed.gov). Interestingly, this is what constitutes “research” for many sport supplement companies. Hence, the term “borrowed research.” Just check the available references provided in the product advertisement (if this is even done). They often have little or nothing to do with the actual product of sale.
The above scenario is certainly applicable to the class of sport supplements known as nitric oxide stimulators. A recent scan of many of the top bodybuilding magazines published during 2008 indicated that several advertisements are devoted solely to this class of sport supplement (range: 9-36; Table 1). Clearly, these agents are extremely popular for athletes, bodybuilders in particular. The following text describes the rationale for use of such products and provides an overview of the scientific evidence for effect of nutritional supplements purported to increase nitric oxide.
NITRIC OXIDE DESCRIBED
Nitric oxide (NO) was initially referred to as endothelium-derived relaxing factor (17), as it was found to result in vasorelaxion of smooth muscle. Nitric oxide is synthesized within the body from the amino acid l-arginine, oxygen, and a variety of other cofactors by a family of enzymes known as nitric oxide synthases (13). A number of important biological processes are influenced by nitric oxide, as reviewed in great detail elsewhere (4,34). In summary, it is known that very high concentrations of nitric oxide favor cell cycle arrest and programmed cell death. This may be at least partly related to the interaction of nitric oxide with superoxide radical, subsequently leading to peroxynitrite, a potent and harmful reactive nitrogen species (3).
On the contrary, brief production of nitric oxide at low (nanomolar) concentrations favors beneficial physiological functions including decreased platelet and leukocyte adhesion, decreased smooth muscle cell proliferation, regulation of neurotransmission and muscle atrophy/hypertrophy, the stimulation of satellite cells, and enhanced blood flow and immune defense (2,4,31,34). The specific mechanism of action of nitric oxide appears mediated by both a cyclic guanosine monophosphate (cGMP)-dependent and cGMP-independent signaling cascade (4). Nitric oxide exhibits these effects while acting as a gaseous chemical compound and has received considerable scientific attention over the past 3 decades since the early work of Furchgott and Zawadzki (18). In fact, nitric oxide was recognized as “molecule of the year” by Science magazine in 1992, and the Nobel Prize in Physiology or Medicine was awarded in 1998 for work related to nitric oxide signaling within the cardiovascular system. Clearly, nitric oxide is of great importance to the scientific community.
In relation to sport supplementation, nitric oxide may be of interest for its potential effects on increasing blood flow, as well as regulating muscle atrophy/hypertrophy. These are the areas of greatest focus as pertaining to advertisements for such products, in particular the potential effect on increasing blood flow. This would be mediated by the action of nitric oxide on vascular smooth muscle cells (4), ultimately promoting vasodilation. It is suggested in most advertisements for such products that the proposed increase in blood flow will result in increased oxygen and nutrient delivery (e.g., amino acids, fatty acids, glucose) to skeletal muscle during exercise. This should aid exercise performance. Additionally, the increased blood flow will be retained during the postexercise period, allowing for enhanced exercise recovery. This should result in muscle hypertrophy. Figure 1 depicts the theoretical basis for such supplementation.
While the above logic appears to make at least some physiological sense based on the known effect of nitric oxide on enhancing blood flow, there exist far too many assumptions with this line of thought that one cannot possibly make these statements with confidence. This is particularly true concerning the actual ability of the product to cause a measurable increase in nitric oxide. Even if this is achieved, the idea that the increased nitric oxide will ultimately lead to enhanced blood flow, which will improve both exercise performance and exercise recovery, is speculative at best.
NITRIC OXIDE AND EXERCISE
As stated above, appropriate and consistent attention to exercise training and dietary intake account for most of the success related to both physique development and physical performance. It should also be known that nitric oxide is increased in response to acute sessions of exercise (8,12,18,20,30) and can be increased as an adaptation to regular exercise training (15,28,35). That is, well-trained individuals may have higher resting circulating nitric oxide than their sedentary counterparts. This is typically determined by the combined measurement of the stable products of nitric oxide metabolism, which itself has a half-life equal to only 3 to 4 seconds. These products include nitrate (NO-3) and nitrite (NNO-2), typically measured in blood or urine. Based on the above, if maximizing the potential benefits of nitric oxide, it seems most important to simply be involved in a program of regular structured exercise. If maximizing circulating nitric oxide is a goal, trainers and coaches should reinforce this with their clients/athletes.
It should be understood that several other mechanisms are involved with regulation of blood flow during and following exercise, as described in detail recently (22,37). These may include flow-mediated dilation; muscle contraction-induced distortion of resistance vessels; alterations in chemicals such as endothelin, adenosine, and prostacyclin; and changes in temperature, pO2, pCO2, and pH. Therefore, even if such products did result in a measurable and reliable increase in nitric oxide, it still remains to be determined what, if any, effect this would have on exercise performance and recovery. In fact, these other mechanisms aside from nitric oxide have been suggested to be primarily responsible for facilitating optimal blood flow redistribution and hyperemia with acute exercise, with nitric oxide playing only a minor role (38). This appears to dampen enthusiasm for use of such products, at least based on the current marketing pitch related to the wonders of increased blood flow.
AGENTS USED TO INCREASE NITRIC OXIDE
There exist a few pharmaceutical agents that have been used with success to either increase nitric oxide biosynthesis or maintain nitric oxide, ultimately promoting vasodilatation (9). These agents include transdermal and sublingual nitrates (often used for patients with cardiac disease), intravenous and oral l-arginine, and intravenous propionyl-l-carnitine (often used for patients with peripheral vascular disease). Other agents that indirectly fall into this category and used for the treatment of erectile dysfunction are drugs such as Viagra® (Pfizer, Inc., New York, NY) and Cialis® (Lilly USA, LLC, Indianapolis, IN). This class of drug has been under investigation recently for the potential performance-enhancing ability, noting improved performance with hypoxia (high-altitude exercise) but not normoxia (sea-level exercise), with a great degree of variability in subjects' response (21). Based on these initial findings, it does not appear that these drugs will improve performance at sea level.
l-arginine is the chief ingredient in most nitric oxide-stimulating dietary supplements, present in a variety of forms and typically at a dosage of 3 grams per serving. This rationale for l-arginine inclusion is based largely on research using intravenous l-arginine, often at dosages of 20 to 30 g. Clearly, l-arginine is the precursor to nitric oxide biosynthesis and has been associated with enhanced vasodilatation (6,19). However, the route of administration in such studies has been intravenous injection and not oral intake. This is obviously a major concern. Studies involving direct comparisons between intravenous and oral l-arginine indicate no effect of oral l-arginine on vasodilatation, which may be attributed to variance in oral l-arginine bioavailability (7), likely due to the fact that oral l-arginine intake is hindered by extensive elimination due to intestinal arginase activity (32). Based on this observation, citrulline, the precursor to l-arginine, has been shown to be more effective than l-arginine in increasing plasma l-arginine concentrations and associated nitric oxide-dependent signaling (32).
Studies involving oral intake of l-arginine at dosages ranging from 10 to 20 g indicate no benefit of this amino acid with regard to increasing circulating nitric oxide or enhancing blood flow (1,11,29). Moreover, there has been some reporting of unpleasant taste and gastric distress with an oral dose of only 10 grams per day (29). That being said, a recent study found that an oral dose of 15 g of l-arginine improved endothelial dysfunction (a measure of blood vessel reactivity) following intake of a high-fat meal (24). This does not imply that blood flow was increased. It was simply decreased to a lesser extent compared to when subjects were provided a placebo, following ingestion of a high-fat meal, which is known to impair blood flow. This agrees with an earlier study using a dosage of 6 grams per day of l-arginine for 10 days prior to a high-fat test meal (26). Neither of these studies included measures of nitric oxide; hence, making assumptions for such an effect based on studies as presented above is highly flawed. This is compounded by the relatively low dosage of l-arginine (e.g., 3 g/serving) provided in most dietary supplements sold on the market today. At this low dosage, it is unlikely that oral intake will have any impact on nitric oxide. In fact, a recent study using 3 grams per day of l-arginine found no increase in nitric oxide availability and actually noted a reduction in exercise time to fatigue in a sample of patients with peripheral arterial disease (38).
In contrast to these findings, a report published in 2006 by Campbell et al. (10) did note a slight improvement in bench press 1-repetition maximum (1-RM) and Wingate cycle test peak power output compared with a placebo, when subjects ingested 12 grams per day of l-arginine α-ketoglutarate (AAKG) over an 8-week intervention period, which included resistance exercise performed 4 days per week. This is the only published study to this author's knowledge to report a performance benefit with l-arginine supplementation, and the findings were negligible with a great degree of subject variability. For example, the mean ± SD increase in bench press 1-RM was 8.82 ± 7.33 kg for AAKG and 2.67 ± 9.11 kg for placebo. Unfortunately, no measure of nitric oxide was included in this study. Finally, one must also consider the suggestion that l-arginine itself may not be the rate-limiting component to nitric oxide biosynthesis (23). Rather, nitric oxide synthase enzymes may be most important. Therefore, adding l-arginine may be futile if the enzymes involved in nitric oxide synthesis are not available in the quantity and at the activity necessary to drive the formation of the molecule.
Based on the above, the scientific evidence does not appear to support the use of l-arginine as a nitric oxide stimulator when provided in oral form, in particular at a low dosage. However, some athletes claim benefit of using nitric oxide-stimulating supplements. Aside from the placebo effect, which has been well described in athletes (36) and nonathletes (16), it is possible that a physiological effect may be observed when using some of the “cocktail” products available in the market. Many of these products contain a variety of ingredients in addition to various forms of l-arginine (e.g., amino acids, creatine, beta-alanine, carbohydrate) that may indeed have a positive effect. In particular, the sugar content of many products may be responsible for some effect because sugar intake results in an insulin spike and insulin has been shown to result in vasodilation (19,33).
PROPIONYL-l-CARNITINE (AND GLYCINE PROPIONYL-l-CARNITINE)
Propionyl-l-carnitine (PLC) is a prescription drug in Europe, used in the treatment of intermittent claudication. Propionyl-l-carnitine has been demonstrated to increase blood nitric oxide in response to 6 grams per day given via intravenous infusion (25). Glycine propionyl-l-carnitine (GPLC) is a molecular bonded form of propionyl-l-carnitine and the amino acid glycine, currently sold as a dietary ingredient/supplement. We have reported that oral intake of GPLC at a dosage of 4.5 grams per day results in increased plasma nitric oxide, as measured by NNO-3 + NNO-3. These findings have been noted in resistance-trained men following a 4-week intervention (5). Glycine propionyl-l-carnitine is currently being used as an ingredient in many finished sport nutrition products sold in the market.
The mechanisms of action for this apparent increase in nitric oxide with PLC and GPLC appear mediated by a decrease in nicotinamide adenine dinucleotide phosphate oxidase activation (27). Nicotinamide adenine dinucleotide phosphate oxidase subsequently leads to superoxide radical generation (39), which in turn can interact with nitric oxide. This may decrease nitric oxide bioavailability, while at the same time lead to the formation of peroxynitrite (3). It has also been reported recently that PLC increases endothelial nitric oxide synthase (14), leading to increased nitric oxide production.
INGREDIENTS VERSUS FINISHED PRODUCTS
When considering the recommendation, purchase, and/or use of nitric oxide-stimulating dietary supplements (or any supplement for that matter), it is important to distinguish between ingredients and finished products, and the science, or lack there of, supporting each. That is, most dietary supplement advertisements include statements such as “the key ingredient found within product X has been shown in clinical studies to result in the desired effect.” This is not the same as data obtained from subjects using the actual finished product of sale. In particular, the route of administration and the dosage used, in addition to the test subjects (or test model) involved in the study, could differ significantly.
For example, if one particular ingredient that may be included within a given product has been shown to result in an increase in nitric oxide when provided via intravenous injection, this may have little to no relevance when consumed by subjects in oral form. Also, if an ingredient has been used with success when administered at a dosage, which is 10 to 20 times greater than what is used in the product of sale, these findings may be meaningless in the context of the finished product. This is further complicated by the use of “proprietary blends” that are commonplace in the dietary supplement market. With such a listing, there is no way of knowing how much of the claimed key ingredients are actually contained with the product. Last, if studies were done using animal models, or done in vitro (e.g., test tube, petri dish), findings cannot be directly applied to a human subject consuming a finished product in oral form. Unfortunately, advertisements for dietary supplements (the nitric oxide category included) use such borrowed research all the time. This “ingredient science” is interesting and may lead to the development of future products, but the “finished product science” must be done before firm conclusions can be made regarding the efficacy of such products being used in oral form by human subjects. In most cases, the ingredient science simply is not enough, largely due to the issues above (e.g., route of administration, dosage, test model).
Nitric oxide-stimulating dietary supplements are widely available and aggressively marketed to the sports/bodybuilding community. Unfortunately, these products have little direct scientific evidence for effect and depend largely on borrowed science related to research done on isolated and intensified dosing of certain ingredients, in particular l-arginine. This, coupled with paid endorsements from top athletes, and a bit of the placebo effect thrown in for good measure, have catapulted this class of supplement to the top in the bodybuilding world. With the exception of one study (5), there exist no published scientific reports to indicate that the dietary supplements currently being marketed as “nitric oxide stimulators” have proven efficacy. Many research questions remain to be answered with regard to this class of dietary supplement, including GPLC. These include questions pertaining to whether such products can reliably (a) stimulate an increase in nitric oxide production, (b) stimulate an increase in blood flow, (c) stimulate an increase in nutrient and oxygen transport to exercising muscle, (d) improve exercise performance and recovery, and (e) increase muscle mass. Such claims are made routinely within the advertisements for such supplements. However, without well-designed research studies focused on the actual product of sale, answers to such questions will remain unknown and this field will remain much more hype than effect.
When athletes are considering the use of nitric oxide-stimulating dietary supplements (or any supplement for that matter), the following questions should be asked. The same applies to trainers or coaches who may be providing recommendations to clients/athletes on the use of such products.
- Have any studies been conducted to test the product's efficacy? And were they performed by an unbiased group? Preferably not by the company selling the product.
- Have the results been published? And if so, where? Preferably in a peer-reviewed scientific journal.
- If studies were conducted, were they performed on a population that represents the potential user? Or were they done in vitro (i.e., test tube), using animals, geriatrics, etc? This is important! What works for one population is not necessarily going to benefit another.
- What is the suggested dosage and how does it compare with the dosage used in the clinical studies?
- How much does the effective dosage cost? Is this cost justified for the potential gain?
- How was the dosage administered in the clinical studies (e.g., oral, intravenous) and is the recommended route of administration the same as for the product of sale?
- What makes the product so much better/more effective than the others?
- Have any comparative studies been done on the product versus competitive products?
- What are the realistic results that the athlete can expect to see after using this supplement?
- Are there any known or possible side effects or drug interactions associated with use of this product? Or will this product put the athlete at jeopardy for testing positive for banned substances?
Answers to the above questions should guide the athlete in the potential use of a particular dietary supplement. When considering use of such products, it is also important to keep in mind that despite the fact that products may not have proven efficacy related to stimulating an increase in nitric oxide (and subsequent blood flow), this does not necessarily imply that the products are ineffective in other areas of sport nutrition. This is particularly true when considering that some products within this class are pre- or post-workout beverages containing other nutrients such as protein and carbohydrate, both of which may be important to exercise performance and recovery.
That being said, when considering that most nitric oxide-stimulating supplements are targeted for the benefits of improved blood flow (i.e., improved muscle pump) and improved exercise performance, athletes might consider other supplements that are known to deliver these benefits, those that have proven efficacy and are more cost effective. One such supplement is creatine monohydrate. More scientific reports are available pertaining to the ergogenic benefits of creatine than any other single supplement. Anecdotal reports from athletes/bodybuilders also indicate that creatine results in an excellent muscle pump. All of this for the wholesale/Internet cost of approximately $15 to $20 per kilogram of creatine. Even at a dosage of 10 grams per day, this amounts to only 15 to 20 cents per day or about $55 to $75 per year. Try to get the same deal for latest nitric oxide-stimulating dietary supplement, for which evidence for effect is questionable at best. The choice here seems rather simple.
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