- Jun 25, 2006
- 5,046
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by Monica Mollica
ome of the most popular supplements today are the so called pre-workout nitric oxide (NO) boosters 1, 2. These contain a panoply of ingredients, but the main one is arginine. The rationale goes that arginine is a nitric oxide (NO) precursor and NO is a potent vasodilator 3, 4, which in turn supposedly will boost blood flow to exercising muscles, performance and recovery. And while arginine supplementation is beneficial for various clinical populations (see below), studies in healthy adults have not unequivocally supported the marketing hype surrounding arginine supplementation and nitric oxide boosters 1, 5, 6. Why? Let’s take a look under the hood…
Some reasons explaining the inefficacy of arginine supplementation and nitric oxide boosters
The popular pre-workout NO boosting supplements rely on the arginine-NO pathway and a lot of theoretical assumptions. Some reason for the conflicting findings on arginine supplementation are that studies have used different routes of administration (oral vs. intravenous), various forms of L-arginine, varying exercise testing protocols, different test subjects (trained vs. untrained, young vs. elderly), and supplement cocktails containing other substances (eg. creatine, beta-alanine, caffeine, carbs etc) that indeed do have performance enhancing effects.
The rationale for L-arginine supplementation is based largely on research using intravenous L-arginine, often at dosage of 30 g. This has no practical relevance since most, if not all, supplements are taken orally. In a direct head-to-head comparison of oral and intravenous L-arginine administration, no effect on vasodilatation was found after oral L-arginine supplementation 7. One reason for this could be the extensive elimination of orally ingested L-arginine due to intestinal arginase activity and low bioavailability 8. This would require intake of very large amounts of L-arginine, which not only has an unpleasant taste, but also can cause gastric problems 9.
The Arginine Paradox
The backbone running the arginine-NO pathway is an enzyme called eNOS (endothelial nitric oxide synthase) 10. One factor that affects the velocity of an enzyme catalyzed reaction is the concentration of the substance the enzyme uses (a.k.a substrate). L-arginine is a substrate for the NOS, which converts L-arginine into NO 11. For eNOS, the Michaelis-Menten (Km) constant (which is nerd speak denoting the substrate concentration with which half the enzyme reaction velocity maximum rate is attained) is about 3 mmol/L 12, whereas the blood L-arginine concentrations in both healthy and diseased individuals ranges from 40 to 100 mmol/L 11. This means that the typical non-supplemented blood level of is high enough to saturate endothelial NOS. And when an enzyme is saturated with substrate (in this case L-arginine) more substrate won’t have an effect on a reaction. Therefore, if you’re healthy, when you supplement L-arginine (even in large dosages) you won’t get more NO from the arginine-NO pathway, because L-arginine is not rate-limiting for eNOS.
However, the story is different in clinical conditions like e.g. high blood pressure 13, 14, elevated cholesterol levels 15, 16, heart disease 17, insulin resistance 18, diabetes 19, 20 and in the elderly population 14, 21, in whom L-arginine supplementation has beneficial effects, possibly due to increased NO production 14. Thus, it appears that L-arginine is a limiting factor for NO synthesis in clinical conditions, but not for healthy individuals.
The term ‘L-arginine paradox’ refers to specific situations in which L-arginine supplementation indeed does stimulate NOS activity and NO production, even when blood arginine levels are within the normal range. One explanation for the L-arginine paradox is the presence of high levels of ADMA (asymmetric dimethylarginine), which is an inhibitor of eNOS 10, 22-24. ADMA is produced as part of the body’s normal metabolism 25-27, but in clinical conditions the ADMA levels are elevated several fold 24. In the presence of elevated blood levels of ADMA, eNOS activity diminishes, resulting in a reduced NO production.
How L-arginine supplementation works in the context of elevated ADMA levels
Because ADMA “displaces” L-arginine and thereby reduces the L-arginine availability for eNOS, the ratio of L-arginine to ADMA determines how much of the L-arginine that is floating around in the blood that will be available for eNOS to use for NO production 28, 29. In conditions with elevated ADMA levels, L-arginine supplementation will antagonize ADMA by re-establishing the L-arginine/ADMA ratio and thereby “re-activating” eNOS and increasing NO production 30. This is supported by studies showing that L-arginine supplementation reverses endothelial dysfunction attributable to high ADMA levels in clinical populations 21, 31-33, and that there exist a direct correlation between the change in L-arginine/ADMA ratio and the change in blood flow mediated dilation (vasodilatation) 8.
How to combat elevated ADMA levels
The importance of ADMA is underscored by the fact that it is considered a novel cardiovascular risk factor 22, 33, 34. ADMA seems to mediate the effect of many risk factors on the NOS pathway. Therefore, blood ADMA levels have been suggested to be an “Über marker”, or an overall risk factor that reflects the summative effect of all risk factors on endothelial and cardiovascular health 26.
Because of this, drug companies are currently fervently trying to develop drugs that lower ADMA levels. As of this writing there is no ADMA specific drug available. The strongest candidate as an ADMA specific drug is DDAH, the enzyme that naturally breaks down ADMA 27, 35, 36, and whose activity is also impaired in the above mentioned clinical conditions. DDAH boosting drugs are still in the research phase of development, and it will likely take many years before they, or any other ADMA lowering drugs hit the market. However, several well known drugs used for diabetes (metformin, rosiglitazone) and high blood pressure (ACE inhibitors, angiotensin receptor antagonists) have been shown to lower ADMA levels 37-40. Today, the only dietary option is L-arginine supplementation for those in need.
Will L-arginine supplementation benefit me?
If you are insulin resistant (have elevated levels of insulin and/or blood glucose), have high blood pressure, elevated blood cholesterol, high homocysteine levels 32, diabetes or cardiovascular disease, and/or passed your middle-age a while ago, L-arginine supplementation will work for you in restoring subpar NO production.
In contrast, if you don’t have any risk factors and, save your money. In the next article I will cover a less well known NO producing pathway, that can benefit both healthy and risk factor affected folks.
ome of the most popular supplements today are the so called pre-workout nitric oxide (NO) boosters 1, 2. These contain a panoply of ingredients, but the main one is arginine. The rationale goes that arginine is a nitric oxide (NO) precursor and NO is a potent vasodilator 3, 4, which in turn supposedly will boost blood flow to exercising muscles, performance and recovery. And while arginine supplementation is beneficial for various clinical populations (see below), studies in healthy adults have not unequivocally supported the marketing hype surrounding arginine supplementation and nitric oxide boosters 1, 5, 6. Why? Let’s take a look under the hood…
Some reasons explaining the inefficacy of arginine supplementation and nitric oxide boosters
The popular pre-workout NO boosting supplements rely on the arginine-NO pathway and a lot of theoretical assumptions. Some reason for the conflicting findings on arginine supplementation are that studies have used different routes of administration (oral vs. intravenous), various forms of L-arginine, varying exercise testing protocols, different test subjects (trained vs. untrained, young vs. elderly), and supplement cocktails containing other substances (eg. creatine, beta-alanine, caffeine, carbs etc) that indeed do have performance enhancing effects.
The rationale for L-arginine supplementation is based largely on research using intravenous L-arginine, often at dosage of 30 g. This has no practical relevance since most, if not all, supplements are taken orally. In a direct head-to-head comparison of oral and intravenous L-arginine administration, no effect on vasodilatation was found after oral L-arginine supplementation 7. One reason for this could be the extensive elimination of orally ingested L-arginine due to intestinal arginase activity and low bioavailability 8. This would require intake of very large amounts of L-arginine, which not only has an unpleasant taste, but also can cause gastric problems 9.
The Arginine Paradox
The backbone running the arginine-NO pathway is an enzyme called eNOS (endothelial nitric oxide synthase) 10. One factor that affects the velocity of an enzyme catalyzed reaction is the concentration of the substance the enzyme uses (a.k.a substrate). L-arginine is a substrate for the NOS, which converts L-arginine into NO 11. For eNOS, the Michaelis-Menten (Km) constant (which is nerd speak denoting the substrate concentration with which half the enzyme reaction velocity maximum rate is attained) is about 3 mmol/L 12, whereas the blood L-arginine concentrations in both healthy and diseased individuals ranges from 40 to 100 mmol/L 11. This means that the typical non-supplemented blood level of is high enough to saturate endothelial NOS. And when an enzyme is saturated with substrate (in this case L-arginine) more substrate won’t have an effect on a reaction. Therefore, if you’re healthy, when you supplement L-arginine (even in large dosages) you won’t get more NO from the arginine-NO pathway, because L-arginine is not rate-limiting for eNOS.
However, the story is different in clinical conditions like e.g. high blood pressure 13, 14, elevated cholesterol levels 15, 16, heart disease 17, insulin resistance 18, diabetes 19, 20 and in the elderly population 14, 21, in whom L-arginine supplementation has beneficial effects, possibly due to increased NO production 14. Thus, it appears that L-arginine is a limiting factor for NO synthesis in clinical conditions, but not for healthy individuals.
The term ‘L-arginine paradox’ refers to specific situations in which L-arginine supplementation indeed does stimulate NOS activity and NO production, even when blood arginine levels are within the normal range. One explanation for the L-arginine paradox is the presence of high levels of ADMA (asymmetric dimethylarginine), which is an inhibitor of eNOS 10, 22-24. ADMA is produced as part of the body’s normal metabolism 25-27, but in clinical conditions the ADMA levels are elevated several fold 24. In the presence of elevated blood levels of ADMA, eNOS activity diminishes, resulting in a reduced NO production.
How L-arginine supplementation works in the context of elevated ADMA levels
Because ADMA “displaces” L-arginine and thereby reduces the L-arginine availability for eNOS, the ratio of L-arginine to ADMA determines how much of the L-arginine that is floating around in the blood that will be available for eNOS to use for NO production 28, 29. In conditions with elevated ADMA levels, L-arginine supplementation will antagonize ADMA by re-establishing the L-arginine/ADMA ratio and thereby “re-activating” eNOS and increasing NO production 30. This is supported by studies showing that L-arginine supplementation reverses endothelial dysfunction attributable to high ADMA levels in clinical populations 21, 31-33, and that there exist a direct correlation between the change in L-arginine/ADMA ratio and the change in blood flow mediated dilation (vasodilatation) 8.
How to combat elevated ADMA levels
The importance of ADMA is underscored by the fact that it is considered a novel cardiovascular risk factor 22, 33, 34. ADMA seems to mediate the effect of many risk factors on the NOS pathway. Therefore, blood ADMA levels have been suggested to be an “Über marker”, or an overall risk factor that reflects the summative effect of all risk factors on endothelial and cardiovascular health 26.
Because of this, drug companies are currently fervently trying to develop drugs that lower ADMA levels. As of this writing there is no ADMA specific drug available. The strongest candidate as an ADMA specific drug is DDAH, the enzyme that naturally breaks down ADMA 27, 35, 36, and whose activity is also impaired in the above mentioned clinical conditions. DDAH boosting drugs are still in the research phase of development, and it will likely take many years before they, or any other ADMA lowering drugs hit the market. However, several well known drugs used for diabetes (metformin, rosiglitazone) and high blood pressure (ACE inhibitors, angiotensin receptor antagonists) have been shown to lower ADMA levels 37-40. Today, the only dietary option is L-arginine supplementation for those in need.
Will L-arginine supplementation benefit me?
If you are insulin resistant (have elevated levels of insulin and/or blood glucose), have high blood pressure, elevated blood cholesterol, high homocysteine levels 32, diabetes or cardiovascular disease, and/or passed your middle-age a while ago, L-arginine supplementation will work for you in restoring subpar NO production.
In contrast, if you don’t have any risk factors and, save your money. In the next article I will cover a less well known NO producing pathway, that can benefit both healthy and risk factor affected folks.