This article is really interesting [Haussinger et al., 1990: (http://www.springerlink.com/content/l2vx314521367706/)], and the authors discuss the way the urea cycle, in the liver, normally consumes a lot of bicarbonate, during the overall conversion of ammonia and bicarbonate into urea and carbon dioxide, and tends to decrease serum bicarbonate. When the liver function of a person becomes impaired, the kidneys dispose of more ammonia in the urine, thereby acidifying the urine and further increasing the serum bicarbonate (which tends to be elevated because of urea cycle dysfunction in liver disease).
This is relevant to supplementation with glutamine and arginine in the context of any number of conditions, including sports nutrition or any other condition in which glutamine and arginine have been used (many different conditions). Glutamine supplementation can increase urinary ammonia loss and elevate serum bicarbonate [Welbourne, 1995: (http://hardcorephysiologyfun.blogspot.com/2009/02/potential-for-hypophosphatemia-or.html)], but this effect of glutamine is, in my opinion, more highly regulated and responsive to changes in serum bicarbonate than the effect of alpha-ketoglutarate, which abnormally elevates the cytosolic, as opposed to intramitochondrial, pool of alpha-ketoglutarate, is. Haussinger et al. (1990) cite reference 53 as evidence that, in people who are already displaying metabolic alkalosis, meaning that the serum bicarbonate is elevated, glutamine supplementation or infusion does not increase urinary ammonia loss (and would therefore not be expected to further elevate serum bicarbonate or abnormally increase urinary phosphate loss). But another message of this and other articles is that this homeostatic functioning of renal glutaminase will, essentially, only function properly in a person whose serum ammonia levels are not elevated. This means that the urea cycle in the liver has to be functioning normally, or the homeostatic stopgap measures for disposing of ammonia, such as in the urine in unusually large amounts, in a manner that is dependent on renal glutaminase activity and could be sensitive to changes in glutamine availability through supplementation, have the potential to create wild fluctuations in serum bicarbonate.
The message of this and the other articles I've been reading is, in my opinion, that arginine supplementation could help to minimize the risk of acid-base disturbances (and the consequent disturbances reductions in serum ionized calcium and serum phosphate that can result from increases in serum bicarbonate, such as could conceivably occur in response to glutamine supplementation) in response to glutamine supplementation. The authors of this article [Feillet et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9686348)] discuss the fact that supplemental L-arginine is used in the treatment of all of the genetic defects, except arginase deficiency, that produce hypofunctionality in urea cycle enzymes. Supplementing with arginine has, in my opinion, major advantages over supplementing with ornithine or citrulline. These advantages are that the biosynthesis of arginine from citrulline requires two moles of ATP per mole of arginine synthesized, and Morris et al. (2004) [see here for reference: (http://hardcorephysiologyfun.blogspot.com/2009/02/contribution-of-glutamine-to-pool-of.html)] referred to this, implicitly, as being a rationale for the use of supplemental arginine under conditions of metabolic stress. Another advantage of arginine is the fact that an increase in the dietary ratio of ornithine to arginine may decrease creatine biosynthesis in the kidneys, via the ornithine-induced inhibition of renal arginine:glycine amidinotransferase (AGAT) activity [see Crim et al. (1976), Stromberger et al. (2003), and Arias et al. (2004), cited here: (http://hardcorephysiologyfun.blogspot.com/2009/02/glutamate-glutamine-cycle-de-novo.html)]. Moreover, arginosuccinate synthetase is the rate-limiting step in the urea cycle, and the provision of arginine effectively bypasses this rate-limiting step and simultaneously provides a source of intracellular, "compartmentalized" ornithine that can enter the urea cycle. This might seem paradoxical, given that arginine essentially provides more nitrogen than ornithine. But it's partly the fact that arginine serves as a kind of metabolic "branch point" substrate that is in high demand by nitric oxide synthase enzymes and by many other enzymes, such as those that use arginine for polyamine biosynthesis, protein synthesis, creatine biosynthesis, etc. A similar rationale applies to the use of L-glutamine [Young and Ajami, 2001: (http://jn.nutrition.org/cgi/reprint/131/9/2449S) (http://www.ncbi.nlm.nih.gov/pubmed/11533293?dopt=Abstract)], as opposed to alpha-ketoglutarate or glutamate (glutamine synthetase consumes ATP, and exogenous glutamine spares glutamine and ATP by limiting the consumption of glutamine and ATP by glutamine synthetase). But there's the additional fact that fairly low doses of calcium alpha-ketoglutarate were shown to produce vomiting and other gastrointestinal symptoms in people in one study, in people with kidney disease [Bro et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9469496)]. Five of 17 people who had taken calcium alpha-ketoglutarate had to drop out of that arm of the trial because of those types of symptoms, and alpha-ketoglutarate reduced both serum ionized calcium and serum phosphate (Bro et al., 1998). I've explained, in past postings, the mechanisms I think are responsible for those effects, and, in my opinion, those reductions in serum ionized calcium and serum phosphate, reductions that may occur in the context of abnormally-elevated ammonia due to liver disease or kidney disease or other states of disease or metabolic or physical stress, are most likely to have been a consequence of the abnormal acceleration, by alpha-ketoglutarate, of urinary acidification (and concomitant elevation of serum bicarbonate) via renal ammonia disposal. And if one has to limit the dosages of alpha-ketoglutarate, because of its gastrointestinal side effects, to doses that are so small as to have only a minimal effect of sparing glutamine at extrarenal sites, that's a major disadvantage, in my opinion.
These concepts are relevant to the potential effects of arginine or glutamine in the brain or in cerebral vascular endothelial cells, but I don't have time to discuss that now. One major point of interaction is between glutamine-dependent, de novo uridine biosynthesis (and also de novo purine biosynthesis, which requires glutamine), at the level of carbamoyl phosphate synthetase II, and the urea cycle. But I also think that type of interaction is relevant in cells that lack the full complement of urea cycle enzymes (cells outside the liver). But impairment of the overall activities of the urea cycle enzymes abolishes, to a significant extent, the feedback inhibition of carbamoyl phosphate synthetase II by uridine triphosphate and uridine diphosphate. This leads to excessive orotate accumulation, and orotate has a multitude of toxic effects and can produce significant ATP depletion, etc. In my opinion, this would suggest the usefulness of arginine and glutamine, in some sort of balanced dosage approach, in combination with uridine, in the context of neuroprotection and other purposes that supplemental uridine has been used or researched in the treatment of. The potential usefulness of exogenous arginine as a strategy for elevating creatine biosynthesis in the brain has been proposed by Arias et al. (2004) [see here for that reference and related references: (http://hardcorephysiologyfun.blogspot.com/2009/02/glutamate-glutamine-cycle-de-novo.html)], and, in my opinion, the use of arginine would be a safer approach for elevating creatine in the brain, such as in the context of psychiatric diseases [see Roitman et al. (2007), cited in that blog posting] than the use of creatine itself would be. I say that for reasons that are too numerous to go into.
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