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The Power of Nitrates - Gym Performance & Muscle Enhancement
A few years ago, several new ingredients hit the market that would become the latest fad for bodybuilders chasing the pump. Arginine (ARG) was the first true ?pump? ingredient that claimed to increase plasma nitric oxide (NO) levels which would lead to increased vasodilation and massive pumps in the gym.
While it's true that arginine is the body?s natural endogenous pathway to increase nitric oxide, supplementation with arginine fell short on the claims. In your body, the amino acid arginine is converted into nitric oxide via the enzyme NO Synthase.
Related - Nitrates: The Freaky-Intense King of Muscle Pumps?
This reaction is a two step process by which arginine reacts with oxygen to form nitric oxide plus citrulline. [1] This process works well in the body when normal amounts of arginine are present. However, arginine also has another metabolic fate in which it binds to the enzyme arginase where it reacts with water and is converted into ornithine and urea. [2]
While arginine has a higher affinity for NOS than arginase, the maximum activity for arginase is 1000x greater than that of NOS. This suggests that both reactions have similar rates of substrate utilization.
So if you take a lot of exogenous arginine, only half of it will go to NOS and produce nitric oxide, while the rest will go to arginase. [3] Also noted was that large amounts of arginine that were needed to elevate nitric oxide levels caused extreme gastric distress and were even shown to lower GH levels post workout (a time where you want high levels of GH). [4]
The ?next big thing? brought to market for increasing nitric oxide levels was the amino acid citrulline. Perhaps the biggest study to back this claim was a 2008 study conducted in Germany that showed oral supplementation with citrulline increased plasma arginine levels more than oral ingestion of arginine. [5] The study showed that subjects who ingested 3g of citrulline had higher plasma levels of arginine and increased nitric oxide and cGMP urinary metabolites vs taking arginine.
As I mentioned earlier, citrulline, along with nitric oxide, is the byproduct of the reaction of arginine and NO Synthase. By ingesting large amounts of citrulline, your body will convert that citrulline back into arginine and then into nitric oxide.
Citrulline supplementation seems to circumvent the issue with arginine competitively binding with arginase. However, citrulline is expensive and studies show the clinical dose needed to improve exercise performance was 8g (of citrulline malate which equates to around 6g of L-citrulline). [6] Is there another option to increase plasma nitric oxide levels that is more effective?
The answer is yes!
Your body has another pathway by which it can create NO called the nitrate-nitrite-nitric oxide pathway. Nitrates (NO3-) taken in through diet can be converted into nitrites (NO2-) via bacteria in your mouth and saliva. Once converted in nitrites, these molecules can be reduced to nitric oxide via nitrite reductase without worrying about side reactions that may decrease nitric oxide production (like Arginase). [7]
There are natural forms of nitrates found in various green leafy vegetables like beet root, lettuce, carrots and collared greens, but not in high enough quantiles to really be viable. For example, you would have to eat almost 500g of beetroot in order to receive around 480mg of nitrates.
However, there is some good research on nitrates from beetroot and improving exercise performance. Studies have shown that ingestion of 500mL of beetroot juice (the most common volume used in studies) increased plasma NO levels by 52%. [8][9] One of the main benefits from nitrates with regards to exercise is improving time to exhaustion and peak power. [10][11][12]
However, for this article I want to focus more on the chemistry and differences between all the amino acid nitrate combination ingredients out. So with large amounts of vegetables required for relatively small doses of nitrates, the industry needed another way to get all the benefits of nitrate supplementation in a cost-effective and practical manner.
The resulting salt is an ionically bound negatively charged NO3- anion with a positively charged AA cation. This bond is quickly broken when the salt is added to water, yielding AA+ and NO3-. The main difference between organic nitrate sources will be the parent AA and its molecular weight. This will determine the amount of nitrates you receive from each combination ingredient.
I believe the first one brought to market was arginine nitrate (ArN).
Arginine has a molecular weight of 174.20g per mole, while the nitrate ion has a molecular weight of 62g per mole. As you can see, the nitrate ion is roughly 3x lower in mass versus arginine.
Mathematically, nitrates comprise 26.2% of the total weight of arginine nitrate, with arginine comprising the remaining 73.8%. That means for every gram of arginine nitrate you consume, you are getting 262mg of nitrate and 738mg of arginine.
In order to get the full benefits from the clinical dose of 700-850mg of nitrates, you would need to take in at least 3g of arginine nitrate. If you consume 3g of arginine nitrate, this would only yield 2.2g of arginine, which about half goes to arginase, leaving you with far less than the effective dose for increasing nitric oxide levels. To my knowledge, at this time there are no clinical studies for arginine nitrate.
Creatine is the most widely studied supplement on the market, whose benefits are unquestioned in sports nutrition and performance. Creatine works by acting as a phosphate donor to ADP to form ATP. It also acts as an osmolyte, meaning it draws water into your cells to keep them hydrated during long bouts of exercise. [13]
Creatine has a molecular weight of 131.13g per mole, while nitrate still has a molar mass of 62g per mole. This means that for every gram of creatine nitrate you take in, you are getting 679mg of creatine and 321mg of nitrate - slightly more than arginine nitrate.
In order get the full benficial dose of nitrates, you would have to consume around 2.5g of creatine nitrate. The clinical dose of creatine (in the form of monohydrate) is 5g, which would require a dose of 7.5g of creatine nitrate! In case you didn't know, CrN is very expensive compared to creatine monohydrate (CM)? Over 30 times more expensive.
With that being said, there is a clinical study on creatine nitrate. The study is a safety study that involved 58 participants who either took 1g, 2g of creatine nitrate or a placebo a day for 28 days. The study showed that in the 2g group, creatinine and BUN levels increased beyond the clinical reference range, but were not statistically significant so I wouldn't worry about that too much. [14]
Betaine acts as a methyl donor to either help eliminate harmful molecules like homocysteine or form S-adenosyl methionine (another methyl donor that helps make creatine endogenously). Betaine is also an osmolyte like creatine and helps regulate cell hydration and tonicity.
Betaine has many ergogenic benefits such as increased power and strength. A 2010 study involving 12 resistance trained athletes were given either 2.5g/d of betaine or a placebo for 14 days and exercise performance was measured. The betaine group showed gains in bench throw power, isometric bench force, vertical jump power and isometric squat force. [15]
A 2011 study demonstrated that 14 days of betaine supplementation resulted in greater post-exercise muscle tissue oxygen saturation vs the placebo. The implications of this may be that betaine may have enhanced Kreb?s cycle efficiency due to its omsoprotective properties and may also improve high-intensity aerobic performance, especially in very hot environments. It stands to reason that betaine may also increase mitochondrial function and improve tissue oxygen consumption.
The molecular weight of betaine is 117.15g per mole and again nitrate is 62g per mole. If you were to ingest 1g of betaine nitrate it would yield 654mg of betaine and 346mg of nitrate. Since the clinical dose of betaine is 2.5g, you would need to consume around 3.9g of betaine nitrate to get the full benefits.
Arginine we established is almost ineffective for raising plasma nitric oxide levels compared to citrulline. While good, citrulline must convert first back to arginine then to nitric oxide, and is only effective at high doses. It doesn't make sense to use 6-8g of citrulline when 550-800mg of nitrates can yield an even better response. On top of that, by using one of these AA nitrates you are also getting the benefits of the parent compound, i.e. creatine or betaine.
Just remember to properly calculate your dose to get the maximum benefits from these organic nitrates. Important to consider before taking ANY nitrates: If you are taking any blood pressure or erectile dysfunction medication, do not use any of these nitrates as they may cause an unsafe drop in blood pressure.
2) Wu G, Morris SM (November 1998). "Arginine metabolism: nitric oxide and beyond". The Biochemical Journal. 336. ( Pt 1): 1?17.
3) Durante, William, Fruzsina K. Johnson, and Robert A. Johnson. "Arginase: a critical regulator of nitric oxide synthesis and vascular function." Clinical and Experimental Pharmacology and Physiology 34.9 (2007): 906-911.
4) Marcell, Taylor J., et al. "Oral arginine does not stimulate basal or augment exercise-induced GH secretion in either young or old adults." Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences 54.8 (1999): M395-M399.
5) Schwedhelm, Edzard, et al. "Pharmacokinetic and pharmacodynamic properties of oral L?citrulline and L?arginine: impact on nitric oxide metabolism." British journal of clinical pharmacology 65.1 (2008): 51-59.
6) Pérez-Guisado, Joaquín, and Philip M. Jakeman. "Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness." The Journal of Strength & Conditioning Research 24.5 (2010): 1215-1222.
7) Lundberg, Jon O., Eddie Weitzberg, and Mark T. Gladwin. "The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics." Nature reviews. Drug discovery 7.2 (2008): 156.
8) Bailey, Stephen J., et al. "Dietary nitrate supplementation reduces the O 2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans." Journal of applied physiology 107.4 (2009): 1144-1155.
9) Vanhatalo, Anni, et al. "Acute and chronic effects of dietary nitrate supplementation on blood pressure and the physiological responses to moderate-intensity and incremental exercise." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 299.4 (2010): R1121-R1131.
10) Cermak, Naomi M., Martin J. Gibala, and Luc JC Van Loon. "Nitrate supplementation?s improvement of 10-km time-trial performance in trained cyclists." International journal of sport nutrition and exercise metabolism 22.1 (2012): 64-71.
11) Murphy, Margaret, et al. "Whole beetroot consumption acutely improves running performance." Journal of the Academy of Nutrition and Dietetics112.4 (2012): 548-552.
12) Bond, Hannah, Lillian Morton, and Andrea J. Braakhuis. "Dietary nitrate supplementation improves rowing performance in well-trained rowers." International journal of sport nutrition and exercise metabolism 22.4 (2012): 251-256.
13) Terjung, Ronald L., et al. "American College of Sports Medicine roundtable. The physiological and health effects of oral creatine supplementation." Medicine and Science in Sports and Exercise 32.3 (2000): 706-717.
14) Joy, Jordan M., et al. "28 days of creatine nitrate supplementation is apparently safe in healthy individuals." Journal of the International Society of Sports Nutrition 11.1 (2014): 60.
15) Lee, Elaine C., et al. "Ergogenic effects of betaine supplementation on strength and power performance." Journal of the International Society of Sports Nutrition 7.1 (2010): 27.
16) Trepanowski, John F., et al. "The effects of chronic betaine supplementation on exercise performance, skeletal muscle oxygen saturation and associated biochemical parameters in resistance trained men." The Journal of Strength & Conditioning Research 25.12 (2011): 3461-3471.
While it's true that arginine is the body?s natural endogenous pathway to increase nitric oxide, supplementation with arginine fell short on the claims. In your body, the amino acid arginine is converted into nitric oxide via the enzyme NO Synthase.
Related - Nitrates: The Freaky-Intense King of Muscle Pumps?
This reaction is a two step process by which arginine reacts with oxygen to form nitric oxide plus citrulline. [1] This process works well in the body when normal amounts of arginine are present. However, arginine also has another metabolic fate in which it binds to the enzyme arginase where it reacts with water and is converted into ornithine and urea. [2]
While arginine has a higher affinity for NOS than arginase, the maximum activity for arginase is 1000x greater than that of NOS. This suggests that both reactions have similar rates of substrate utilization.
So if you take a lot of exogenous arginine, only half of it will go to NOS and produce nitric oxide, while the rest will go to arginase. [3] Also noted was that large amounts of arginine that were needed to elevate nitric oxide levels caused extreme gastric distress and were even shown to lower GH levels post workout (a time where you want high levels of GH). [4]
The ?next big thing? brought to market for increasing nitric oxide levels was the amino acid citrulline. Perhaps the biggest study to back this claim was a 2008 study conducted in Germany that showed oral supplementation with citrulline increased plasma arginine levels more than oral ingestion of arginine. [5] The study showed that subjects who ingested 3g of citrulline had higher plasma levels of arginine and increased nitric oxide and cGMP urinary metabolites vs taking arginine.
As I mentioned earlier, citrulline, along with nitric oxide, is the byproduct of the reaction of arginine and NO Synthase. By ingesting large amounts of citrulline, your body will convert that citrulline back into arginine and then into nitric oxide.
Citrulline supplementation seems to circumvent the issue with arginine competitively binding with arginase. However, citrulline is expensive and studies show the clinical dose needed to improve exercise performance was 8g (of citrulline malate which equates to around 6g of L-citrulline). [6] Is there another option to increase plasma nitric oxide levels that is more effective?
The answer is yes!
Your body has another pathway by which it can create NO called the nitrate-nitrite-nitric oxide pathway. Nitrates (NO3-) taken in through diet can be converted into nitrites (NO2-) via bacteria in your mouth and saliva. Once converted in nitrites, these molecules can be reduced to nitric oxide via nitrite reductase without worrying about side reactions that may decrease nitric oxide production (like Arginase). [7]
There are natural forms of nitrates found in various green leafy vegetables like beet root, lettuce, carrots and collared greens, but not in high enough quantiles to really be viable. For example, you would have to eat almost 500g of beetroot in order to receive around 480mg of nitrates.
However, there is some good research on nitrates from beetroot and improving exercise performance. Studies have shown that ingestion of 500mL of beetroot juice (the most common volume used in studies) increased plasma NO levels by 52%. [8][9] One of the main benefits from nitrates with regards to exercise is improving time to exhaustion and peak power. [10][11][12]
However, for this article I want to focus more on the chemistry and differences between all the amino acid nitrate combination ingredients out. So with large amounts of vegetables required for relatively small doses of nitrates, the industry needed another way to get all the benefits of nitrate supplementation in a cost-effective and practical manner.
Enter Ron Kramer and Nitrates
Organic nitrates were introduced to the supplement world a few years ago, when he bought the patent for chemically combining nitrates with amino acids. All of the molecules I will be talking about contain the exact same form of nitrates, via a chemical reaction involving said amino acid (AA) and nitric acid.The resulting salt is an ionically bound negatively charged NO3- anion with a positively charged AA cation. This bond is quickly broken when the salt is added to water, yielding AA+ and NO3-. The main difference between organic nitrate sources will be the parent AA and its molecular weight. This will determine the amount of nitrates you receive from each combination ingredient.
I believe the first one brought to market was arginine nitrate (ArN).
Arginine Nitrate
Arginine nitrate is a salt which is synthesized from adding nitric acid to arginine. The resulting salt is an ionically bound negatively charged NO3- ion with a positively charged arginine ion.Arginine has a molecular weight of 174.20g per mole, while the nitrate ion has a molecular weight of 62g per mole. As you can see, the nitrate ion is roughly 3x lower in mass versus arginine.
Mathematically, nitrates comprise 26.2% of the total weight of arginine nitrate, with arginine comprising the remaining 73.8%. That means for every gram of arginine nitrate you consume, you are getting 262mg of nitrate and 738mg of arginine.
In order to get the full benefits from the clinical dose of 700-850mg of nitrates, you would need to take in at least 3g of arginine nitrate. If you consume 3g of arginine nitrate, this would only yield 2.2g of arginine, which about half goes to arginase, leaving you with far less than the effective dose for increasing nitric oxide levels. To my knowledge, at this time there are no clinical studies for arginine nitrate.
Creatine Nitrate
One of the more popular organic nitrates out now is creatine nitrate (CrN). Creatine nitrate is prepared the same way that arginine nitrate is, forming the same salt molecule that dissociates in water into creatine and nitrate ions.Creatine is the most widely studied supplement on the market, whose benefits are unquestioned in sports nutrition and performance. Creatine works by acting as a phosphate donor to ADP to form ATP. It also acts as an osmolyte, meaning it draws water into your cells to keep them hydrated during long bouts of exercise. [13]
Creatine has a molecular weight of 131.13g per mole, while nitrate still has a molar mass of 62g per mole. This means that for every gram of creatine nitrate you take in, you are getting 679mg of creatine and 321mg of nitrate - slightly more than arginine nitrate.
In order get the full benficial dose of nitrates, you would have to consume around 2.5g of creatine nitrate. The clinical dose of creatine (in the form of monohydrate) is 5g, which would require a dose of 7.5g of creatine nitrate! In case you didn't know, CrN is very expensive compared to creatine monohydrate (CM)? Over 30 times more expensive.
With that being said, there is a clinical study on creatine nitrate. The study is a safety study that involved 58 participants who either took 1g, 2g of creatine nitrate or a placebo a day for 28 days. The study showed that in the 2g group, creatinine and BUN levels increased beyond the clinical reference range, but were not statistically significant so I wouldn't worry about that too much. [14]
Betaine Nitrate
The last AA nitrate I want to talk about is betaine nitrate (BN). Betaine nitrate is the combination of betaine anhydrous with nitric acid. Betaine, also known as trimethylglycine, is a metabolite of choline and like nitrates, is also found in beetroot.Betaine acts as a methyl donor to either help eliminate harmful molecules like homocysteine or form S-adenosyl methionine (another methyl donor that helps make creatine endogenously). Betaine is also an osmolyte like creatine and helps regulate cell hydration and tonicity.
Betaine has many ergogenic benefits such as increased power and strength. A 2010 study involving 12 resistance trained athletes were given either 2.5g/d of betaine or a placebo for 14 days and exercise performance was measured. The betaine group showed gains in bench throw power, isometric bench force, vertical jump power and isometric squat force. [15]
A 2011 study demonstrated that 14 days of betaine supplementation resulted in greater post-exercise muscle tissue oxygen saturation vs the placebo. The implications of this may be that betaine may have enhanced Kreb?s cycle efficiency due to its omsoprotective properties and may also improve high-intensity aerobic performance, especially in very hot environments. It stands to reason that betaine may also increase mitochondrial function and improve tissue oxygen consumption.
The molecular weight of betaine is 117.15g per mole and again nitrate is 62g per mole. If you were to ingest 1g of betaine nitrate it would yield 654mg of betaine and 346mg of nitrate. Since the clinical dose of betaine is 2.5g, you would need to consume around 3.9g of betaine nitrate to get the full benefits.
Putting It All Together
As I?ve stated many times, I am a fan of these amino acid nitrate compounds, specifically because I am a huge fan of nitrates for vasodilation and pumps. Nitrates are far superior than arginine and citrulline in elevating nitric oxide levels, simply because of the different pathways they use to convert to nitric oxide.Arginine we established is almost ineffective for raising plasma nitric oxide levels compared to citrulline. While good, citrulline must convert first back to arginine then to nitric oxide, and is only effective at high doses. It doesn't make sense to use 6-8g of citrulline when 550-800mg of nitrates can yield an even better response. On top of that, by using one of these AA nitrates you are also getting the benefits of the parent compound, i.e. creatine or betaine.
Just remember to properly calculate your dose to get the maximum benefits from these organic nitrates. Important to consider before taking ANY nitrates: If you are taking any blood pressure or erectile dysfunction medication, do not use any of these nitrates as they may cause an unsafe drop in blood pressure.
References
1) Knowles RG, Moncada S (March 1994). "Nitric oxide synthases in mammals". Biochem. J. 298 (2): 249?58.2) Wu G, Morris SM (November 1998). "Arginine metabolism: nitric oxide and beyond". The Biochemical Journal. 336. ( Pt 1): 1?17.
3) Durante, William, Fruzsina K. Johnson, and Robert A. Johnson. "Arginase: a critical regulator of nitric oxide synthesis and vascular function." Clinical and Experimental Pharmacology and Physiology 34.9 (2007): 906-911.
4) Marcell, Taylor J., et al. "Oral arginine does not stimulate basal or augment exercise-induced GH secretion in either young or old adults." Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences 54.8 (1999): M395-M399.
5) Schwedhelm, Edzard, et al. "Pharmacokinetic and pharmacodynamic properties of oral L?citrulline and L?arginine: impact on nitric oxide metabolism." British journal of clinical pharmacology 65.1 (2008): 51-59.
6) Pérez-Guisado, Joaquín, and Philip M. Jakeman. "Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness." The Journal of Strength & Conditioning Research 24.5 (2010): 1215-1222.
7) Lundberg, Jon O., Eddie Weitzberg, and Mark T. Gladwin. "The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics." Nature reviews. Drug discovery 7.2 (2008): 156.
8) Bailey, Stephen J., et al. "Dietary nitrate supplementation reduces the O 2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans." Journal of applied physiology 107.4 (2009): 1144-1155.
9) Vanhatalo, Anni, et al. "Acute and chronic effects of dietary nitrate supplementation on blood pressure and the physiological responses to moderate-intensity and incremental exercise." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 299.4 (2010): R1121-R1131.
10) Cermak, Naomi M., Martin J. Gibala, and Luc JC Van Loon. "Nitrate supplementation?s improvement of 10-km time-trial performance in trained cyclists." International journal of sport nutrition and exercise metabolism 22.1 (2012): 64-71.
11) Murphy, Margaret, et al. "Whole beetroot consumption acutely improves running performance." Journal of the Academy of Nutrition and Dietetics112.4 (2012): 548-552.
12) Bond, Hannah, Lillian Morton, and Andrea J. Braakhuis. "Dietary nitrate supplementation improves rowing performance in well-trained rowers." International journal of sport nutrition and exercise metabolism 22.4 (2012): 251-256.
13) Terjung, Ronald L., et al. "American College of Sports Medicine roundtable. The physiological and health effects of oral creatine supplementation." Medicine and Science in Sports and Exercise 32.3 (2000): 706-717.
14) Joy, Jordan M., et al. "28 days of creatine nitrate supplementation is apparently safe in healthy individuals." Journal of the International Society of Sports Nutrition 11.1 (2014): 60.
15) Lee, Elaine C., et al. "Ergogenic effects of betaine supplementation on strength and power performance." Journal of the International Society of Sports Nutrition 7.1 (2010): 27.
16) Trepanowski, John F., et al. "The effects of chronic betaine supplementation on exercise performance, skeletal muscle oxygen saturation and associated biochemical parameters in resistance trained men." The Journal of Strength & Conditioning Research 25.12 (2011): 3461-3471.