DURHAM, N.C. -- For more than 130 years, doctors have prescribed nitroglycerin for relief of chest pain without a clear knowledge of how it actually worked. Now, not only have researchers from Howard Hughes Medical Institute (HHMI) and Duke University Medical Centerfrom Duke University Medical Center and the Howard Hughes Medical Institute (HHMI) solved this age-old riddle, they have also shed light on the second major mystery surrounding nitroglycerin -- why patients eventually develop a tolerance to the drug's effects.

Shortly after heart patients take nitroglycerin, the blood vessels supplying the heart muscle relax, allowing oxygen-rich blood to nourish the heart and relieve the pain. While it is known that nitric oxide -- a breakdown product of nitroglycerin -- plays a critical role regulating blood vessel relaxation, scientists still did not know the mechanism by which nitric oxide is generated from the nitroglycerin molecule, which in fact shows little resemblance to nitric oxide.

The research team led by Jonathan Stamler, M.D., HHMI investigator at Duke, found 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.

While researchers in the past have searched for such an enzyme in different tissues, the Duke team found that the biochemical reaction that breaks down nitroglycerin takes place in mitochondria, a compartment within cells commonly known as the cell's "powerhouse." The enzyme is called mitochondrial aldehyde dehydrogenase (mALDH), and only in mitochondria can the nitric-oxide-related product of the enzyme get further processed to blood vessel-relaxing nitric oxide.

"For more than 100 years, doctors have been prescribing nitroglycerin without a clue how it works," Stamler said. "And for the past 30 years scientists have been lo
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Contact: Richard Merritt
merri006@mc.duke.edu
919-684-4148
Duke University Medical Center
3-Jun-2002