Interactions of Phosphate Metabolism With Energy Metabolism and Adenosine Metabolism

These are some articles showing that phosphate availability can be an important factor that determines the rates of salvage of purine nucleotides and nucleosides, the adenylate charge, and the rate of deamination of adenosine to inosine [Matsumoto et al., 1979: (http://www.jbc.org/cgi/reprint/254/18/8956.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/479172); Lockett et al., 1995: (http://www.ncbi.nlm.nih.gov/pubmed/8579734); (http://scholar.google.com/scholar?hl=en&q=energy+%22inorganic+phosphate%22+salvage+purine+OR+adenylate)]. Matsumoto et al. (1979) discussed the fact that inorganic phosphate [Pi, or PO4(3-)] normally inhibits adenosine monophosphate (AMP) deaminase activity, thereby preventing the catabolism of adenosine to inosine. This catabolism, however, can serve to maintain the energy charge, paradoxically, during the inhibition of energy metabolism (Matsumoto et al., 1979). But even when ATP levels are being maintained "normally," the sequestration or loss of intracellular phosphate tends to lead to the loss of adenosine nucleotides (reference 6, cited in 1979). Maj et al. (2000) found that the adenosine-induced inhibition of adenosine kinase (AK) activity, which is a major purine salvage enzyme in the brain and other tissues, decreases as the inorganic phosphate concentration increases. AK is sometimes viewed as being "bad" in the context of cerebral ischemia, and AK inhibitors can reduce brain damage due to ischemia by maintaining adenosine availability, etc. That's another reason that the provision of phosphate in the form of ATP disodium or another purine nucleotide might be advantageous. Phosphate depletion tends to produce a loss of adenosine (and, by extension, guanosine) nucleotides, and phosphate supplementation could have a mixture of beneficial and less-than-beneficial effects, particularly in the short term, on purine metabolism in the brain, for example. Increasing AK activity (meaning the phosphorylation of adenosine) without providing more exogenous adenosine could tend to decrease adenosine availability for cerebral blood flow autoregulation [Sciotti and Van Wylen, 1993: (http://www.ncbi.nlm.nih.gov/pubmed/8436611); (http://scholar.google.com/scholar?hl=en&q=%22adenosine+kinase%22+brain). It's partly because the concentrations of adenosine, both intracellularly (and extracellularly), are normally far lower than the Km of AK for adenosine. The same argument could be made in the case of the phosphate-mediated inhibition of AMP deaminase. Under conditions of low-level ischemia, as in a person with ATP depletion or purine nucleotide depletion (because of repeated cycles of ischemia or pronounced activation of the noradrenergic stress-response system in the brain), the degradation of AMP to IMP can, paradoxically, be "good," up to a point. In any case, there can even be strange short-term effects, in my opinion, of ATP disodium that could be explained, in part, by those paradoxical aspects of adenosine metabolism. Additionally, some few days may be required for changes in A1 adenosine receptor density or sensitivity to occur, even though extracellular adenosine levels are generally kept almost constant (in part by A1 adenosine receptor activation) [Andresen et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10490889)]. For example, A1 adenosine receptor antagonists tend to increase extracellular adenosine (Andresen et al., 1999) and can also have mood elevating effects or the like. Although the steady-state levels of extracellular adenosine and the sensitivities of adenosine receptors will generally adapt efficiently, in my opinion, to changes in stimulus-evoked increases in extracellular adenosine (exogenous ATP would be expected to primarily or almost exclusively augment stimulus-evoked extracellular adenosine concentrations and not steady-state extracellular adenosine levels), those adaptations could, in my opinion, require a day or two to take place. In my experience, there was some kind of threshold dosage, in the short term, above which there were no transient periods of somnolence or the like. I don't even know how I'd describe that type of thing, but my point is that there's some steady state that's reached and that there could be, in my opinion, potential for complex interactions with phosphate homeostasis. And the other point was that the use of sodium phosphate could disturb adenosine metabolism in the short term (and potentially the long term), even if one could not say that the effects are exclusively "bad."