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Nutrition Support Blog: The Next Big Thing ?

Posted by SF8N at Sep 07, 2012 10:40 AM |
September 7, 2012
Nutrition Support Blog:  The Next Big Thing ?

by Joe Krenitsky, MS, RD

Every few years there seems to be some new compound that is proclaimed to be at the root of all illness.  In the 80’s it was all about cholesterol, then it was LDL, later it was all about reducing homocysteine.  While serum increases in these biologic compounds can be strongly associated with disease, reducing concentrations of the offending agent does not always have the degree of impact expected. In regards to homocysteine, there does not appear to be any benefits to reducing homocysteine concentrations with vitamin therapy. 

One of the hot “new” compounds being researched is “asymmetric dimethylarginine” (ADMA).  In the last several years research has linked increased serum ADMA with a number of diseases, and in the last several months alone there have been publications linking ADMA with heart failure, all cause cardiovascular mortality, renal failure, rheumatoid arthritis, hepatorenal syndrome (in cirrhosis), non-alcoholic liver disease, polycystic ovarian syndrome, peripheral artery disease, diabetes, hypertension, sepsis, pulmonary hypertension and more (yes, seriously).  The full explanation for how and why ADMA is such a bad player is way too long to describe here, but the (over) simplified version is that ADMA inhibits the production of nitric oxide, which creates endothelial dysfunction and oxidative stress.

The nutrition link with this compound is that nitric oxide is derived from the amino acid arginine, and supplementation with arginine might possibly be beneficial in conditions of elevated ADMA.  However, there is a surprising complexity associated with arginine supplementation, that has even been described as the “Arginine Paradox”.1  The paradox is that although cells have about 25 times the arginine needed to saturate all of the sites for nitric oxide production, increasing arginine stimulates more nitric oxide (a bit like finding out your car drives twice as fast with ¾ tank of gas, than it does with ½ tank of gas).  Of course, nothing is ever that simple, and researchers have found that supplementing arginine also leads to increased breakdown of arginine from arginase, so that the more you take, the less is available for nitric oxide production over time.  A randomized study of arginine supplementation after a heart attack also appeared to increase mortality, so in practice (as well as theory), there may be more drawbacks than benefits to arginine supplements.2 

A new and promising area of research is the amino acid L-citrulline.  Citrulline, as we all remember from Biochem, is a vital part of the urea cycle (arginine-ornithine-citrulline), and is metabolized to arginine.  It appears that supplementation of L-citrulline may be more effective for increasing nitric oxide production than supplementation of arginine, and a number of exciting studies appear to be in the works.3  L-citrulline is also being investigated as a potential agent to increase protein synthesis and exercise capacity in the elderly, so I expect we may be hearing much more about L-citrulline in the near future (and you thought you would never use that back in Biochem!).  Of course, we will need more randomized studies before we will really know if L-citrulline supplements will have real benefits and/ or side-effects, and only time will tell if the hoopla about ADMA is a breakthrough in our understanding of illness, or just another flash in the pan because it is (another) case of association, and not cause-and-effect.  In the meantime, you may want to brush up on your knowledge of the urea cycle and practice saying things like “carbamoyl phosphate” and “arginosuccinate” when all of the inevitable questions about citrulline pop up.


1.   Dioguardi FS. To give or not to give? Lessons from the arginine paradox. J Nutrigenet Nutrigenomics. 2011;4(2):90-98.

2.   Schulman SP, Becker LC, Kass DA, et al.  L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial.  JAMA. 2006;295(1):58-64.

3.   Schwedhelm E, Maas R, Freese R, et al.  Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism.  Br J Clin Pharmacol. 2008;65(1):51-59.



“In theory, there is no difference between theory and practice; In practice, there is.”

- Chuck Reid


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