For a century or more, how nitroglycerin relieved the pain of angina was largely a mystery. About 25 years ago, the basic explanation began to take shape. The compound provides an external source for nitric oxide, NO, a signaling molecule that dilates blood vessels, providing relief from the effects of clogged arteries--a respite that lasts only a few minutes.

	ENZYME SLEUTHS Stamler (left) and Chen DUKE UNIVERSITY PHOTO

Research at Duke University Medical School is now bringing clarity to the process. The enzyme mitochondrial aldehyde dehydrogenase converts nitroglycerin to 1,2-glyceryl dinitrate and nitrite (NO₂^–), predominantly in mitochondria, according to biochemist and physician Jonathan S. Stamler, a Howard Hughes Medical Institute investigator at Duke; postdoc Zhiqiang Chen; and cardiologist Jian Zhang [Proc. Natl. Acad. Sci. USA, 99, 8306 (2002)].

Nitrite is a chemically reasonable intermediate in the conversion of nitroglycerin to NO, but studies going back for more than 100 years indicate that cells don't convert nitrite to NO, nor will nitrite dilate blood vessels. "But that's because the earlier researchers weren't looking in mitochondria," Stamler explains. Enzymes found within these specialized organelles can reduce nitrite to NO, he says.

The studies also explain why nitroglycerin's benefits are so fleeting. Mitochondrial aldehyde dehydrogenase can process only very small amounts of nitroglycerin, the researchers find. "At higher doses, nitroglycerin oxidizes the active-site thiols of the enzyme," Stamler explains. "It destroys the machinery that generates NO bioactivity, and cells need many hours to repair the damage."

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Copyright © 2002 American Chemical Society