Nitric Oxide Stimulating Dietary Supplements
Introducing Glycine Propionyl-L-Carnitine (GPLC)
What Is Nitric Oxide?
Nitric oxide (NO), initially known as endothelium derived relaxing factor (EDRF), is biosynthesized within the body from L-arginine and oxygen by a variety of nitric oxide synthase enzymes (Collier and Vallance, 1991). Nitric oxide is a gaseous chemical compound that acts as an important signaling molecule within the human body.
Nitric oxide has been shown to decrease platelet and leukocyte adhesion, as well as to decrease the proliferation of smooth muscle cells. These effects are important within blood vessels.
Recent evidence also indicates that NO may be involved in both glucose and fatty acid oxidation (Jobgen et al., 2006). Although, perhaps the most well studied effect of NO is in facilitating vasodilation (opening of blood vessels).
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Nitric Oxide is a free form gas that is produced in the body and is used by the body to communicate with other cells in the body.
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The endothelium (inner layer) of blood vessels is involved in NO production, which acts on vascular smooth muscle cells to promote vasodilation. For this reason alone, nitric oxide has received considerable attention over the past 20+ years from scientists. In fact, NO was recognized as "molecule of the year" by Science in 1992. Additionally, the Nobel Prize in Physiology or Medicine was awarded in 1998 to Robert Furchgott, Louis Ignarro, and Ferid Murad for their discoveries related to NO.
Over the past 5 years in particular, NO has received a great deal of attention from health and fitness enthusiasts, as well as from sports supplement companies who widely market products claiming to increase NO production. In this regard, the primary desired effect is the potential increase in blood flow.
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Exercise And Nitric Oxide:
The demands for increased blood flow with acute strenuous exercise are significant. Although several mechanisms are available to allow for optimal blood flow redistribution with acute exercise, NO indeed plays a major role.
While supplement companies market products targeted at increasing NO, it should be understood by readers that both acute and chronic exercise have been reported to increase circulating NO. This is often determined by the combined measurement of nitrate+nitrite (NOx), which are stable products of the rapidly degraded NO.
Specifically, blood concentrations of NO increase in response to strenuous single bouts of exercise (Bode-Boger et al., 1994; Clarkson et al., 1999), a finding that is evident for both dynamic (Hickner et al., 1997) as well as for isometric (Gilligan et al., 1994) exercise.
Studies involving chronic exercise training performed 3-4 days per week have also noted an increase in resting levels of NO, as measured by NOx (Edwards et al., 2004; Poveda et al., 1997; Tordi et al., 2006).
What this means is that individuals who exercise on a regular basis have an enhanced production of NO at rest, which may help explain some of the positive health and performance outcomes apparent in exercise trained compared to sedentary individuals.
Obviously, if enhancing NO is of importance, regular structured exercise should be a component of an individual's routine, regardless of the use of NO stimulating supplements.
Traditional Drugs/Dietary Supplements & Nitric Oxide
Aside from exercise, pharmaceutical agents have been used with success to induce NO biosynthesis, with the end goal of promoting vasodilation (Burgaud et al., 2003). Such agents are often used in response to various types of health problems.
In some studies, treatments have included high dosages of the NO precursor amino acid, L-arginine, which has been delivered via intravenous injection (at least in those studies demonstrating a benefit).
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Arginine is a semi-essential amino acid. It is a building block of protein that performs a myriad of physiological functions. It is a known precursor of the gas nitric oxide.
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A simple review of those studies that do report a potential benefit of L-arginine in this regard is what constitutes the "research" performed by most supplement companies marketing NO stimulating products. Indeed, actual testing of the various products of sale using a controlled research design is, for the most part, nonexistent.
It is evident that the majority of such products contain various forms of L-arginine as the chief ingredient. Unfortunately, as discussed below, this may not be appropriate when considering all variables know to affect the response to L-arginine treatment (e.g., dosage, route of administration, species studied).
Equally important, although L-arginine is the precursor to NO biosynthesis, it has been suggested that this amino acid is not the rate limiting component (Kurz and Harrison, 1997) and that nitric oxide synthase enzymes may be most important to NO biosynthesis. Therefore, adding excess L-arginine may do little to promote increased NO production, as most individuals already have adequate L-arginine available for NO biosynthesis. What they may need is an increase in certain enzymes that appear to ultimately control NO production.
The supposed "effect" that individuals may experience when using many of the marketed products may be more dependent on the sugar contained within the product, as opposed to the L-arginine. This is because sugar intake results in an insulin spike, and insulin itself has been shown to yield a vasodilating effect (Giugliano et al., 1997; Steinberg et al., 1994).
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Despite this, it is evident that dietary supplements marketed to increase NO production are rampant within the supplement industry. In fact, a quick scan of many of the popular bodybuilding magazines indicates that in any given month there can be more than 30 pages of advertisements that focus solely on this particular class of supplements!
As with many dietary supplements, the scientific evidence for effect for these products is virtually nonexistent. Of course, some of the chief ingredients found within some of these products may have been shown to result in a measurable increase in NO or an increase in blood flow. But a careful review of the original investigations indicates that the dosing suggested by the manufacturer of the product is often FAR less than that used in the original investigation.
More importantly, the route of administration is often different. That is, many original investigations using a given ingredient have used intravenous injection and not oral intake, as is being marketed by supplement companies.
This is of particular importance, as L-arginine at an oral dosage of only 10 grams per day has been noted to have an unpleasant taste and in some cases result in [temporary side effects] (Robinson et al., 2003).
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It has also been reported that oral intake of L-arginine of 20+ grams per day results in arginine absorption that is highly variable across subjects, and does not result in any significant increase in vasodilation (Adams et al., 1995; Chin-Dusting et al., 1996), unlike findings from many studies involving intravenous injection.
Other work involving direct comparisons between intravenous and oral intake of L-arginine agrees with these findings (Bode-Boger et al., 1998), indicating no effect of oral L-arginine intake on vasodilation, partly due the fact that oral L-arginine bioavailability is only ~68%.
Based on the available evidence, it seems unlikely that oral L-arginine intake will result in any improvement in blood flow. Lastly, some of the original investigations have used animals (typically rodents) as test subjects and not humans, or have involved experiments in vitro (i.e., outside of a living organism).
Generalizations to humans cannot always be made from such studies. Collectively, the fact remains that no nutritional supplements marketed to increase NO have been shown in a controlled laboratory study involving human subjects to increase blood levels of NO. That is, until recently.
Glycine Propionyl-L-Carnitine & Nitric Oxide
Glycine Propionyl-L-Carnitine (GPLC) is a USP grade dietary ingredient which consists of a molecular bonded form of propionyl-L-carnitine and one of the carnitine precursor amino acids, glycine. It is marketed as GlycoCarn® through Sigma-tau HealthScience.
Two recent studies have demonstrated an increase in blood levels of NOx with oral GPLC intake, at a daily dosage of 4.5 grams (Bloomer et al., 2007; in press). These findings agree with other recent work using PLC exclusively (Lofreddo et al., 2007) which demonstrated an increase in blood NOx in response to 6 grams per day of PLC given via intravenous infusion.
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Two Recent Studies Have Demonstrated An Increase
In Blood Levels Of NOx With Oral GPLC Intake.
The first study to use GPLC involved previously sedentary men and women who were assigned to supervised aerobic exercise with or without treatment for eight weeks (Bloomer et al., in press).
A significant increase in resting levels of blood NOx was noted for subjects receiving GPLC compared to placebo (in a double blind design). Subjects who received GPLC were also noted as having lower levels of lipid peroxidation, a measure of free radical mediated oxidation of lipids. This is important, as increased free radical production is associated with impaired NO bioavailability.
The second study to use GPLC involved resistance trained men who were assigned to GPLC and a placebo for four weeks each, with a two week washout period between each four week phase—also using a double blind design (Bloomer et al., 2007).
At the end of each four week phase, resting blood samples were obtained, in addition to blood samples following static forearm exercise (used to induce a further increase in NO). Blood NOx was noted to be higher in response to the forearm exercise with GPLC compared to placebo, a finding that may have implications related to enhanced blood flow during acute bouts of exercise.
Need For Further Research
If a given oral dietary supplement is in fact capable of stimulating an increase in circulating NO (to date, GPLC is the only such ingredient reported in the scientific literature to do so), to observe a desired effect it must be assumed that:
- The increase in circulating NO will cause an increase in blood flow to working skeletal muscle.
- The increase in blood flow will be associated with an increase in oxygen and nutrient delivery.
- The increase in oxygen and nutrient delivery will promote:
- An increase in work capacity during exercise.
- Enhanced recovery post exercise.
Study pertaining to these variables in human subjects using this class of nutritional supplements is indeed in its infancy. Continued work over the next couple of years will hopefully provide new insight into addressing these interesting and important issues.
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The Increase In Oxygen And Nutrient Delivery
Will Promote Enhanced Recovery Post Exercise.
It is well documented that NO acts in blood vessel dilation and improved blood flow. For athletes and fitness enthusiasts, this is essential because greater blood flow is associated with increased oxygen and nutrient delivery to skeletal muscle.
This may be important both during the exercise bout (to aid in performance and to improve the muscle "pump"), as well as during the recovery period (to aid in nutrient delivery to help facilitate exercise recovery). In this way, products aimed at increasing NO may prove helpful.
To date, GPLC is the only dietary ingredient reported to promote such an effect, which may be enhanced if consumed with carbohydrate rich meals, as insulin has been shown to promote vasodilation (Giugliano et al., 1997; Steinberg et al., 1994) and to enhance carnitine retention (Stephens et al., 2006; 2007), which may apply to GPLC (a novel form of carnitine).
Continued research on this ingredient will provide additional information pertaining to the potential for enhanced blood flow, and subsequent enhanced performance and recovery associated with exercise.
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