Mitochondrial Enzyme Breaks Down Nitroglycerin

Nitroglycerin has been used for more than 130 years for relief of chest pain without a clear knowledge of how it actually works. Furthermore, it was not known why some patients became tolerant to nitroglycerin and ceased to be affected by it.

What has been known is that nitroglycerin must be metabolized to release nitric oxide. However, neither the site of this metabolism nor the enzymes responsible have been identified. Now, a study published online June 4, 2002, in the Proceedings of the National Academy of Sciences describes the discovery of an enzyme that not only breaks down nitroglycerin and releases a nitric-oxide related molecule, but whose action is suppressed in blood vessels made tolerant after repeated doses of nitroglycerin.

The study was conducted by researchers from Duke University (Durham, NC, USA), who isolated a nitrate reductase from macrophage mitochondria that specifically catalyzes the formation of 1,2-glyceryl dinitrate and nitrite from nitroglycerin, leading to production of cGMP and relaxation of vascular smooth muscle both in vitro and in vivo. They identified the enzyme as mitochondrial aldehyde dehydrogenase (mtALDH).

A new approach was taken in this study in that the researchers screened many types of cells for the ability to metabolize nitroglycerin rather than to focus on vascular cells. They found that macrophages were a rich source of this activity. A detailed study of these macrophages led to the finding that the breakdown of nitroglycerin occurred in the mitochondria. Looking then at mitochondria from vascular cells, they found that indeed mtALDH was present and mediated the release of nitric oxide from nitroglycerin.

As to why some patients develop tolerance to nitroglycerin, Dr. Jonathan Stamler, who led the Duke study, explained, "In general, cells do not work as well after being exposed to nitroglycerin. It appears that after several reactions, the enzyme is used up, and over time the mitochondria become totally depleted of active enzyme and are therefore unable to break down nitroglycerin.”

Understanding the molecular mechanism of nitroglycerin bioactivation and tolerance may lead to the design and development of novel nitrovasodilator drugs that do not cause tolerance.



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