In this article, Levine et al. (1992) [Levine et al., 1992: (http://radiology.rsnajnls.org/cgi/reprint/185/2/537.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/1410369)] used magnetic resonance spectroscopy (MRS) scans to look at the "phosphocreatine index," which is [PCr]/([PCr] + [Pi]), such that Pi = inorganic phosphate, as a way of quantifying the energy states of cells in different parts of the brain. Levine et al. (1992) also calculated the pH in the brain, by comparing measurements of Pi and PCr, and found a number of changes in the correlations between different pairs of indices in people who had recently had strokes. The authors noted that acidosis generally decreases the PCr/Pi ratio (Levine et al., 1992), and they found that, during the acidotic conditions of ischemia, in the brains of people who had recently (within days or weeks, depending on the patient) had strokes, the pH correlated directly with the phosphocreatine index and with the PCr content (as indicated by the magnitude of the MRS signal) and inversely with Pi. I'm not quite sure how to interpret a change in the intracellular inorganic phosphate levels, but I guess that makes sense that the pH would decrease as the Pi increases. The intracellular (and extracellular, to some extent) Pi levels are thought to generally increase in parallel with the hypoxia or ischemia-associated increases in intracellular AMP levels [Gorman et al., 1997: (http://ajpheart.physiology.org/cgi/reprint/272/2/H913.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/9124455)], and Gorman et al. (1997) also found that a "steady-state," or prehypoxic, depletion of the intracellular phosphocreatine contents, in the hearts of guinea pigs, caused the hypoxia-induced release of Pi and adenosine to decrease. Gorman et al. (1997) also noted that Pi stimulates glycolytic activity, and there's a considerable amount of research showing that the depletion of intracellular levels of either Pi or organic phosphates causes fairly severe deficits in glycolytic and oxidative ATP synthesis. Brautbar et al. (1983) [Brautbar et al., 1983: (http://www.ncbi.nlm.nih.gov/pubmed/6620852)] found that, in response to dietary phosphate depletion/restriction in rats, the total intracellular protein contents of creatine kinase (CK, "creatine phosphokinase"), among the rats, correlated directly with the intracellular Pi concentrations, and both the intracellular Pi levels and creatine kinase levels were decreased in response to dietary Pi depletion. The authors also cited research, on the last page, discussing the capacity of Pi to activate glutaminase and phosphofructokinase activities, and the activities of those enzymes are important in relation to energy metabolism, especially during ischemia or hypoxia. The decrease in the CK protein content was drastic (more than 50 percent) (Brautbar et al., 1983) and is really interesting, in part because the authors only found, in response to dietary Pi restriction, nonsignificant reductions in the intracellular adenosine nucleotide levels and inconsistent changes in the PCr levels (Brautbar et al., 1983). The authors apparently equated the CK protein content with CK activity, and I'm not sure that that would always be a valid assumption (the CK protein content might not correlate linearly with the CK activity, because of phosphorylation of CK by AMPK or by effects of pH on CK activity, etc.). But in humans with renal failure, phosphate supplementation increased ATP levels in the skeletal muscle, compared to controls, but did not change serum phosphate/phosphorus levels. I'd bet that Pi depletion produces changes in PCr or in the PCr index in humans as well as in animals.
Lyoo et al. (2003) [Lyoo et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/12850248)] found that the levels of Pi in the brains of humans increased by more than 9 percent in response to creatine (Cr) supplementation, but the authors evidently didn't find any differences in pH between the control and Cr-supplemented groups. Lyoo et al. (2003) also found decreases in the beta-nucleotide triphosphate (beta-NTP) levels (a reflection of ATP levels) and marginal increases in PCr levels, and that trend toward an increase in the PCr/ATP ratio is generally consistent with the increases in PCr/NTP ratio that have been found, in the brains of humans, in response to triacetyluridine or SAM-e administration (http://hardcorephysiologyfun.blogspot.com/2009/06/deoxyribonucleotides-in-mtdna-depletion.html). Lyoo et al. (2003) and others have explained that change in terms of a mass action effect (it's not really ATP depletion and is thought to be evidence of an increase, not a decrease, in intracellular high-energy phosphate levels) that would operate in the overall equilibrium of the intramitochondrial CK enzymatic reaction (the more important CK equilibrium, as I recall) (it's noteworthy that the intramitochondrial ADP pool can be somewhat independent of the cytosolic ADP pool, however):
Cr + ATP <---> PCr + ADP + H(+)
I think that ATP disodium is much more potent than SAM-e and would require lower dosages (expressed both in terms of mg of adenosine that can be derived from ATP disodium, in comparison to mg adenosine that can be derived from SAM-e, and in terms of the dosages of ATPNa2 and SAM-e) to produce effects. Low-dose creatine (1-3 grams/day) has potential, in my opinion, to work in concert with ATPNa2 and uridine or triacetyluridine or cytidine (pyrimidines), etc. Those are just my opinions. Pyrimidines have repeatedly been shown to increase the retention of intracellular purine nucleotides during hypoxia or other metabolic insults. I was going to discuss the research showing that CK activity, induced by cellular creatine depletion, generally appears [O'Gorman et al., 1996: (http://www.ncbi.nlm.nih.gov/pubmed/8816948)] or has been shown to [Dzeja et al., 1996: (http://www.ncbi.nlm.nih.gov/pubmed/8662747)] vary inversely with adenosine kinase activity in different cell types. That effect could be partially due to changes in inorganic phosphate availability, but the relationships between the intracellular Pi levels and adenosine kinase (AK) and creatine kinase activities are likely to be complex. Some research has shown that Pi produces allosteric activation of AK (http://hardcorephysiologyfun.blogspot.com/2009/07/these-are-some-articles-showing-that.html), but Gorman et al. (1997) found that Pi inhibited the activity of AK that had been taken from the hearts of guinea pigs. I don't have time to go into the potential mechanisms, but one has to take into account the adenylate charge and the activating effects that AMP (or an increase in the AMP/ATP ratio) and Pi can have on glycolytic enzymes, etc. It's interesting that Gorman et al. (1997) discussed an index that I've almost never seen researchers use. They referred to the cytosolic phosphorylation potential as being an index, or ratio, that correlates (positively) with the energy state of the cell [similar to the adenylate charge, or {[ATP] + 0.5[ADP])/([ATP] + [ADP] + [AMP]), with [ ]'s referring to the intracellular molarities of the nucleotides}. The cytosolic phosphorylation potential is (log [ATP]/[ADP][Pi]). That's sort of similar to the phosphocreatine index, but it seems that one might expect the phosphocreatine index to vary almost inversely with the cytosolic phosphorylation potential.
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