Interactions of Acid-Base Homeostasis with the Metabolism of Adenosine Nucleotides, Inorganic Phosphate, and Phosphocreatine

These articles [Katz et al., 1988: (http://www.ncbi.nlm.nih.gov/pubmed/3394819); Korzeniewski, 2006: (http://www.jbc.org/cgi/content/full/281/6/3057)(http://www.ncbi.nlm.nih.gov/pubmed/16314416)] discuss some interesting aspects of acid-base homeostasis, especially in relation to the metabolism of adenosine nucleotides. Katz et al. (1988) derived this equation to show the relative stability of the intracellular pH in the face of changes in the arterial pH:

arterial blood pH (pHart) = 0.23 pHi + 5.43

Korzeniewski (2006) discussed an interesting "equation" that may shed light on the quantitative impact of a shift in the creatine kinase equilibrium (the author actually includes Pi in the expression and refers to it as the Lohman reaction) on intracellular pH. In the creatine kinase equilibrium (:

PCr ---> Cr + Pi + (s)H(+),

where (s) = 0.63 - (pHcytosolic - 6.0) x 0.43

I assume that's 0.63 - [(pHcytosolic - 6.0)(0.43)]

Katz et al. (1988) also found that the intracellular ratio of ATP to inorganic phosphate (ATP/Pi) was about 7 in the hearts of beagles but noted that earlier research had shown the ratio to be about 1.5 in dogs. Katz et al. (1988) also found that *free* intracellular Pi was about 0.8 mM (800 uM) in the beagle heart, and that's much lower than the levels of total, intracellular Pi found in either humans or rats. For example, Brautbar et al. (1983) [Brautbar et al., 1983: (http://www.ncbi.nlm.nih.gov/pubmed/6620852)] found that the total intracellular Pi levels in the skeletal muscles of rats ranged from about 7.5 mM (7500 uM) to 16 mM (16000 uM), and Ambuhl et al. (1999) [Ambuhl et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10561144)] found intracellular inorganic phosphate levels of 31-40 mM in the muscles of humans. Hitchins et al. (2001) [Hitchins et al., 2001: (http://ajpheart.physiology.org/cgi/content/full/281/2/H882)(http://www.ncbi.nlm.nih.gov/pubmed/11454594?dopt=Abstract)] found a value of 2.85 mM for the intracellular Pi in the skeletal muscles of rats and cited research showing values ranging from 2.7 to 4.9 mM in the skeletal muscles of rats. Just looking at the skeletal muscle data from normal rats, on a normal diet (given that the Pi levels in the range of 7.5 mM, as found by Brautbar et al. (1983), were measured in rats given a phosphate-deficient diet), it looks like the total intracellular Pi levels are somewhere between about 3.3 and 20 times the free intracellular Pi values, but it's difficult to make precise comparisons. Brautbar et al. (1983) noted that the value of 0.8 mM is close to the Km values for the binding of Pi to various enzymes, including respiratory chain enzymes (collectively, apparently). Brautbar reported very high total cellular protein contents (~ 290 mg protein/g ww muscle tissue), and the usual conversion factor assumes that there is about 100-150 mg protein/g ww tissue. That could substantially alter some of those conversion factors.

Korzeniewski (2006) found evidence that the deamination of AMP to inosine monophosphate (IMP), by AMP deaminase, can help to prevent metabolic acidosis during hypoxia or exercise. One reason for that, as discussed by Korzeniewski (2006), is that an abundance of ADP and, especially, AMP can directly or indirectly activate glycolytic enzymes, such as phosphofructokinase, and thereby produce intracellular acidification [Mader, 2003: (http://www.ncbi.nlm.nih.gov/pubmed/12527960)], and Korzeniewski (2006) also noted that, during hypoxia, more ADP is consumed through glycolytic activity than through respiration (i.e. the phosphorylation to ATP) but that the total intracellular ADP levels are more consistently maintained, under a variety of different cellular conditions, than the ATP levels are. Korzeniewski (2006) cited research showing that creatine depletion can lead to reductions in AMP deaminase activity, and that depletion of total intracellular creatine could conceivably impair the resistance of the brain (or muscle) to hypoxic or ischemic insults.

Incidentally, an alternate interpretation of the MRS data showing that exogenous creatine, SAM-e, and triacetyluridine can increase the phosphocreatine/nucleoside triphosphate (PCr/NTP) ratios in the brains of humans would be to say that all of those compounds have been found to increase the intracellular adenosine nucleotide levels [Ronca-Testoni et al., 1985: (http://www.ncbi.nlm.nih.gov/pubmed/4087306); (http://hardcorephysiologyfun.blogspot.com/2009/01/details-on-nucleotides-bioavailability.html); (http://hardcorephysiologyfun.blogspot.com/2009/05/uridine-induced-maintenance-of-glycogen.html)] . Researchers have also suggested that exogenous adenosine, especially (and also guanosine), exert cardioprotective effects and increase the intracellular PCr/Cr ratio (and, probably, the PCr/ATP ratio) by maintaining the free ADP levels, particularly intramitochondrially, during ischemia [Satoh et al., 1993: (http://www.ncbi.nlm.nih.gov/pubmed/8173706); (Meyer et al., 2006: (http://www.jbc.org/cgi/reprint/281/49/37361)(http://www.ncbi.nlm.nih.gov/pubmed/17028195?dopt=Abstract), discussed here: (http://hardcorephysiologyfun.blogspot.com/2009/03/creatine-cr-phosphocreatine-pcr-and.html)] . One might expect an increase in the intracellular ADP levels, even in the absence of an increase in the adenylate charge [(ATP + 0.5ADP)/(ATP+ADP+AMP)], to be accompanied by, either in opposition to or independently of the mass-action effect that an increase in the intramitochondrial creatine levels has been suggested to have, on the PCr/ATP and PCr/Cr ratios (http://hardcorephysiologyfun.blogspot.com/2009/08/interactions-in-metabolism-of-creatine.html) (the suggestion has been that creatine usually increases those ratios via a mass action effect, but I've cited research showing the opposite effect in past postings [Ceddia and Sweeney, 2004: (http://jp.physoc.org/cgi/reprint/555/2/409)(http://www.ncbi.nlm.nih.gov/pubmed/14724211?dopt=Abstract), cited and discussed here: (http://hardcorephysiologyfun.blogspot.com/2009/03/creatine-cr-phosphocreatine-pcr-and.html)]), a reduction in the ATP/ADP ratio and an increase in the PCr/NTP ratio. Korzeniewski (2006) discussed the fact that the ADP pool is more consistently maintained during metabolic insults, as discussed above, and creatine is known to stimulate respiration by, in large part, helping to maintain the intramitochondrial ADP levels and the recycling of ADP, back into the mitochondrial matrix. That function of the phosphocreatine "shuttle" is especially important during metabolic insults.