Nitric Oxide as a Xanthine Oxidase Inhibitor

This article [Maxwell et al., 2001: (http://content.onlinejacc.org/cgi/content/full/38/7/1850) (http://www.ncbi.nlm.nih.gov/pubmed/11738284?dopt=Abstract)] shows that an acute increase in nitric oxide production can decrease serum uric acid levels. In that article, the researchers used L-arginine to increase nitric oxide production, and L-arginine is a substrate for the inducible nitric oxide synthase (iNOS) enzyme, expressed in endothelial cells and numerous other cell types, and endothelial nitric oxide synthase (eNOS) enzyme. This type of effect is assumed to be desirable in the context of hyperuricemia, and it may be desirable for some people. One message of this article is that the traditional explanation of hyperuricemia [that it results from the underexcretion of urate by the kidneys] may underestimate the extent to which ischemia, in which a reduction in nitric oxide availability tends to occur, contributes to hyperuricemia (by disinhibiting xanthine oxidase activity). Nitric oxide inhibits xanthine oxidase activity, and this is sort of the background for the use of inosine in multiple sclerosis. People with multiple sclerosis tend to have elevated blood levels of NOx (nitrate + nitrite, etc.), higher uric acid levels are associated with lower NOx levels in the blood, and inosine is meant to decrease iNOS-derived nitric oxide by elevating serum uric acid levels. But this effect of nitric oxide would help provide a mechanistic explanation for the elevated NOx levels in people with multiple sclerosis (the nitric oxide could be inhibiting xanthine oxidase, etc.). Excessively-high nitric oxide levels are almost guaranteed to increase peroxynitrite production, and uric acid is arguably the primary peroxynitrite scavenger in humans. But high nitric oxide levels also inhibit mitochondrial function and could interfere with de novo purine biosynthesis in endothelial cells and, at least in the long term, reduce uric acid levels by that type of mechanism. There are some articles showing that serum ferritin is positively correlated with serum uric acid levels, but that is pretty clearly a bad thing. I remember the authors suggested that the high serum ferritin levels were producing a toxic inhibition of nitric oxide production and thereby disinhibiting xanthine oxidase activity (and increasing uric acid levels). But that's an extreme example, and inosine elevates uric acid by a completely different set of mechanisms. No one is suggesting that elevating serum ferritin levels would be a good way to elevate uric acid production.