The authors of this article [Fogh-Andersen et al., 1993: (http://www.clinchem.org/cgi/reprint/39/1/48.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/8419057)] showed that the binding of calcium to albumin increases as the pH of the blood increases, and the increases in calcium binding are especially pronounced as the pH increases above 6.5 (Figure 3 shows that). The slope of the curve showing the increase in binding of calcium per unit of increase in pH is roughly constant and steep, up to a pH of about 9 (supraphysiological). This might be one mechanism that could account for acute (or more slowly-emerging, for that matter) decreases in serum calcium that have sometimes been found in response to large dosages of phosphate. Exogenous phosphate could increase ammonium (acid) excretion, and this could increase blood pH and increase the binding of calcium to albumin. Maybe that effect wouldn't decrease total serum calcium, though, but, assuming the effect occurred, could decrease serum ionized calcium. In people who had exhibited laboratory-confirmed hypophosphatemia or other evidence of phosphate depletion, for example, phosphate administration increased renal acid excretion [that's mainly ammonium, or NH4(+)] [Kohaut et al., 1977: (http://www.ajcn.org/cgi/reprint/30/6/861.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/17294)]. Kohaut et al. (1977) noted that hyperkalemia had previously been found to occur in association with metabolic acidosis, but excessive elevations in serum phosphate have been associated with hyperkalemia (and low serum phosphate is associated with metabolic acidosis). That would seem to be paradoxical, but acidosis has actually been associated with hyperphosphatemia (http://scholar.google.com/scholar?hl=en&q=hyperphosphatemia+acidosis). So it's complex, as one might expect. I'm not going to read about the mechanisms by which lactic acidosis might contribute to hyperphosphatemia, but acidosis can also occur in the context of hypophosphatemia, as in diabetic ketoacidosis [Fitzgerald, 1978: (http://www.ncbi.nlm.nih.gov/pubmed/348032)]. Fitzgerald (1978) and others have noted that bicarbonate administration can be disastrous in people who are hypophosphatemic or even depleted of intracellular phosphate, in part because elevations in the pH of the blood both increase phosphate excretion, such as by increasing the proportion of tubular-fluid phosphate that exists as HPO4(2-) and thereby impairing phosphate reabsorption [Mercado et al., 1975: (http://www.pubmedcentral.nih.gov/picrender.fcgi?doi=10.1172/JCI108219&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/172529)] and also decreasing intracellular 2,3-diphosphoglycerate (2,3-DPG) in red blood cells (RBC's) (Fitzgerald, 1978), but also because increases in serum bicarbonate, according to Fitzgerald (1978), decrease the dissociation of oxygen from hemoglobin in a manner that is independent of the decrease in oxygen "unloading" from hemoglobin that results from RBC 2,3-DPG depletion (Fitzgerald, 1978). Fitzgerald (1978) also cites research, on page 3, showing that alkalosis (due to bicarbonate administration or an increase in serum bicarbonate) increases the transport of phosphate into cells, and I guess that could help to explain the hyperphosphatemia of lactic acidosis. But, over time, the serum phosphate that is not transported into cells would be expected to be excreted and therefore lost, in response to intermittent elevations in serum phosphate (such as in response to exercise, which acutely increases serum phosphate, in association with lactic acidosis), and that could lead to and account for the association of hypophosphatemia with lactic acidosis. But part of it could be that intracellular phosphate depletion tends to decrease oxidative metabolism, and that could reduce lactate oxidation, etc. Mercado et al. (1975), cited above, found that the decrease in serum ionized calcium levels in response exogenous bicarbonate (the pH effect on albumin binding, as the authors discussed) and that the decrease in serum calcium levels caused an increase in parathyroid hormone (PTH) secretion and, hence, in urinary phosphate excretion (Mercado et al., 1975) (because PTH increases urinary phosphate excretion). But Mercado et al. (1975) also noted that bicarbonate can act "directly" on the tubular fluid and increase the proportion of dibasic/divalent phosphate [HPO4(2-)] in relation to monobasic/monovalent phosphate [H2PO4(-)] (dibasic phosphate is evidently not reabsorbed as efficiently as monobasic phosphate is) (Mercado et al., 1975). Bichara et al. (1990) [Bichara et al., 1990: (http://www.pubmedcentral.nih.gov/picrender.fcgi?pmid=2166755&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/2166755)] found evidence that HCl administration, producing acidosis, can acutely increase parathyroid hormone concentrations and, hence, acid excretion and phosphate excretion, etc. Exercise produces acidosis, which could increase serum phosphate by reducing phosphate uptake into cells, but hyperventilation (as in response to acidosis) has generally been associated with decreases in serum phosphate [Young et al., 1973: (http://circ.ahajournals.org/cgi/reprint/47/6/1313.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/4541156)]. I guess one way of looking at that is to say that hyperventilation can lead to a decrease in the partial pressure of CO2 in the blood (pCO2) and, hence, to an increase in blood pH (hypocapnic alkalosis) [Neill and Hattenhauer, 1975: (http://circ.ahajournals.org/cgi/reprint/52/5/854.pdf)], and that could increase phosphate uptake into cells. But during intense exercise, the lactic acidosis should simultaneously, or eventually (after prolonged exercise), decrease phosphate uptake and produce the elevations in serum phosphate that exercise is known to produce. But then the excess serum phosphate would be lost in the urine, etc. Neill and Hattenhauer (1975) note that dyspnea (shortness of breath, which can stimulate hyperventilation) not-infrequently produces hypocapnic alkalosis (presumably by acutely increasing the respiratory rate, inappropriately or appropriately), and dyspnea is known to be a sort of common side effect of excessive dosages of phosphate (or a transient effect of high dosages). I can't try to think about this anymore, right now. It's too complicated. "Why do you, reader of the blog, care about this stuff. God, I don't know how to explain all of these mechanisms. Do you really care about this junk? Why are you asking me?" That's a bit of a joke.
It's complicated, and Bichara et al. (1990) discussed the capacity of hypercalcemia to increase bicarbonate reabsorption and produce alkalosis, etc. These articles basically show, when viewed together, that increases in the ratio of phosphate intake to calcium intake could increase acid excretion (perhaps as a result of the increase in blood pH) and increase the pH of the blood and that those changes could be both a cause and consequence of the increases in PTH levels that are associated with increases in phosphate intake, relative to calcium intake. Over time, the concomitant decreases in intracellular and serum magnesium, for example, could impair the renal responsiveness to PTH hormone and also blunt PTH secretion (or impair the regulation of PTH release, in a general sense) and lead to derangements in acid-base metabolism. But the point is that changes in phosphate availability can have very complex effects on acid-base metabolism and plasma electrolytes. I also came across an interesting article showing that acute elevations in serum calcium produce a strong natriuretic effect, and increases in serum phosphate have tended to be associated with the opposite change (with hypernatremia, in extreme cases). But I won't go into that.
I can't get the full text of this article [Chobanian et al., 1997: (http://www.ncbi.nlm.nih.gov/pubmed/9336702)], but I have a feeling that Chobanian et al. (1997) might mention something about the capacity of an increase in inorganic phosphate availability, to the proximal tubules, to activate glutaminase and thereby increase acid secretion (and produce alkalosis or elevations in serum bicarbonate). Glutamine can increase serum bicarbonate in humans, but I seem to remember that the effect is dependent on the levels of alpha-ketoglutarate in the cytosol in cells in different parts of the renal distal tubules or proximal tubules. I think that glutamine may be able to decrease serum phosphate by increasing blood pH (thereby increasing phosphate uptake into cells), but the glutamine-induced increases in serum bicarbonate and in the blood pH are partially dependent upon and activated by inorganic phosphate (?), etc.
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