This article is great [Rosenfeldt et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9794090)], and it's about uridine and not orotic acid. Orotic acid ("orotate") is a precursor of uridine but is generally toxic to the liver, in my opinion (http://scholar.google.com/scholar?q=%22fatty+liver%22+orotate+OR+orotic&hl=en&lr=), and those effects are, paradoxically, the opposite of those of uridine. Uridine has been used to treat fatty liver disease and decreases orotate formation by causing the uridine-nucleotide-mediated inhibition carbamoyl phosphate synthetase II, etc. Rosenfeldt et al. (1998) found that exogenous uridine maintained the glycogen content in the heart, increased the lactate output from the heart, and prevented much of the loss of adenine nucleotides from the heart during hypoxia. There's a typo that shows up in a couple of places, but the authors knew what they were talking about. The article is fantastic. But the concentration of uridine is listed as having been 17 mM, and the authors mean 17 uM (micromolar). The authors refer to the 17 uM concentration in the discussion section, but the mM concentration showed up in the results section. That's the Greek letter "mu," which can be an "m" in fonts other than symbol font, etc.
But the authors' analysis of the metabolic effects of uridine is really terrific. They measured the lactate output and the amount of glycogen formed and estimated that uridine had increased the rate of glucose uptake by about 50 percent but had not increased the minimal level of oxygen uptake that had occurred during the experiment. They discuss similar research and discuss the fact that the uridine-induced stimulation of glycolysis and glucose uptake (the glycogen concentration was almost double the concentration in the hearts subjected to hypoxia in the absence of uridine) is likely to have produced the uridine-induced increase in purine salvage during hypoxia. The total amount of purine nucleotides that was lost during hypoxia was almost cut in half by uridine. 17 uM is not much higher than the normal physiological plasma concentrations of uridine in humans. The major circulating pyrimidine in humans is uridine, but the major circulating pyrimidine in rats is cytidine. That's the reason the baseline plasma uridine concentration is so low in the rats. There's a lot of other research showing that nucleotides can increase glucose uptake and increase lactate output, but the effects are more complex than that.
These effects of uridine on glycogen formation and glucose uptake and even lactate output help to explain its supposed antidepressant and neuroprotective effects in humans and animals. Researchers have used uridine or its prodrugs to treat depression in a number of trials, and it's been used to treat mitochondrial disorders (encephalopathy and cardiomyopathy due to mitochondrial dysfunction, etc.). But the effects of uridine and other nucleotides are generally quite different from something like AICAR, even though other nucleotides, such as adenosine, have sometimes been shown to enhance AMPK activation (phosphorylation) and activity (by their effects of maintaining the total adenine nucleotide pool or increasing the intracellular AMP concentration more than the intracellular concentrations of other adenine nucleotides), much as AICAR activates AMPK [AMPK activation occurs when specific residues on it are phosphorylated, and the activity of AMPK is its phosphorylation of its target proteins, such as phosphofructokinase, etc.] ([Jaswal et al., 2007: (http://0-ajpheart.physiology.org.library.pcc.edu/cgi/reprint/292/4/H1978)(http://www.ncbi.nlm.nih.gov/pubmed/17172269)]. The concentration of adenosine used in that experiment was 500 uM, however, and that's a supraphysiological concentration. It's by no means a toxic concentration, because adenosine exerts various trophic effects on endothelial cells up to 1000 uM. But the extracellular adenosine concentrations don't usually exceed about 100 uM. The effects of nucleotides on AMPK activation and and activity are likely to depend on the concentrations used, and it's also important to consider the effects of nucleotides on the phosphocreatine to creatine (PCr/Cr) ratio. Many other articles show that uridine, alone or in combination with exogenous purine nucleotides, increases the PCr/Cr ratio. That effect would tend to produce allosteric inhibition of AMPK activity, etc. The main issue I have with AMPK activators is not that AMPK activation per se is "bad." In fact, the inhibition of AMPK activity or activation by specific, drug inhibitors produces toxic effects during ischemia. It's fairly clear that AMPK activation plays a role in maintaining glycolytic activity during hypoxia or ischemia. But my problem is with this assumption that "more" AMPK activation and activity is always going to be "better," and it's evident, in my opinion, that this is not always (or even usually) going to be the case, especially in the long term. This is a great article that discusses some of these issues with research on AMPK in the context of ischemia and elevated contractile activity in the heart [Dyck and Lopaschuk, 2006: (http://jp.physoc.org/content/574/1/95.full.pdf+html)(http://www.ncbi.nlm.nih.gov/pubmed/16690706?dopt=Abstract)].
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