Monday, July 7, 2008

Nitrite and Ischaemia

Embarrassingly, I didn't know the precise meaning of the word Ischaemia (written Ischemia by Americans) until Early March this year. That's quite a confession for the son of two doctors. Basically, ischaemia occurs when blood supply is cut off in a blood vessel. For instance, a clot could occlude the vessel and lead to ischaemia. Anyhow, this is a massive problem in today's world. Millions of chaps suffer from this and quite a few die from it as well. Kumar et al. wrote an interesting paper in the Proceedings of the National Academy of Sciences in which they prescribe the systemic administration of Nitrites as a possible treatment for ischaemia.

Now, Nitrites can be reduced to Nitric Oxide (NO). NO is a very important signalling molecule in the body and it is involved in things ranging from immune response to angiogenesis (formation of new blood vessels). Incidentally, Viagra functions by modulating NO production in the body. Mazzone and Carmeliet, who reported Kumar et al.'s findings in the 26th June 2008 issue of Nature, point out that NO modulates Vascular Endothelial Growth Factor (VEGF) which may result in angiogenesis. Also, VEGF helps in the increased synthesis of NO, presumably by upregulating Nitric Oxide Synthetase. Thus, a positive feedback loop is created.

Now you might be wondering how this is safe. After all, as Mazzone and Carmeliet point out, NO in large quantities is dreadful. For instance, No messes with haemoglobin's oxygen carrying capacity and also disrupts cytochrome c oxidase. Furthermore, reactive oxygen species (such as free radical superoxides) are known to react with NO to make peroxynitrite (ONOO-). Read the article by Pál Pacher, Joseph S. Beckman and Lucas Liaudet at
They talk about how peroxynitrites are involved in aging, hypertension, and Atherosclerosis. Basically, this species can cause tremendous oxidative damage, particularly to the cell's DNA and proteins.

However, NO doesn't work indiscriminately. This is the beauty of the thing. In vessels with a high oxygen concentration, Nitrites gets oxidised to nitrates. However, in occluded vessels, where the oxygen levels are low, nitrites get reduced to NO and angiogenesis gets initiated, thereby helping ease the ischaemic conditions. This makes it possible to administer the NO non-specifically, perhaps even orally. The challenge is to find the perfect NO concentration that avoids high peroxynitrite concentrations and is sufficient to promote angiogenesis at the same time.

How much time do you give it?

1 comment:

The Wanderer said...

Very interesting - incidentally, even I had not known the exact meaning of Ischaemia till I read your blog (though I did know vaguely about it being related to blocked blood vessels, primarily from my understanding of IHD).

You've discussed here the very fine balance of advantages and potential hazards associated with use of Nitrites as a method to handle Ischaemia - the balance is interesting; even more intriguing is the manner in which NO behaves in Oxygen-deprived and Oxygen-rich conditions. The thought of an orally administered drug for such purposes is surely most reassuring.

Let's see how many more years the research community takes before they manage to strike the right balance on the dose and the method of administration of Nitrites to combat Ischaemia.