MONDAY, June 3, 2002 (HealthDayNews) -- This story is dynamite. Literally.
It's about a just-reported solution to a medical mystery that has puzzled doctors for more than a century, one that began when workers in the Swedish factory of Albert Nobel who had heart problems reported that being on the job made them feel better, but that they were also experiencing headaches.
Nobel was getting rich making dynamite, an explosive he invented by combining unstable nitroglycerin with diatomaceous earth to create a product that could be used in construction without risk to life and limb. Nobel wasn't very happy when the military realized dynamite could be used in destructive ways. He used the money he made from dynamite to establish annual prizes for, among other things, efforts for world peace.
Doctors wondered why Nobel's workers felt better on the job, and also why they were suffering from headaches. They eventually realized that nitroglycerin in the factory air was widening blood vessels, which helped the heart but caused pain in the brain.
Nitroglycerin quickly became a staple of cardiovascular medicine, and it has remained that ever since.
However, there has always been one problem with it. The beneficial effects of nitroglycerin don't last. The drug's effect begins to wear off, and doctors must then resort to a "nitrate-free interval," which means stopping treatment for a while. No one understood why patients developed a tolerance to the drug.
Now a team of researchers, headed by Dr. Jonathan S. Stamler, a professor of medicine at Duke University Medical Center, reports the puzzle has been solved.
Stamler and his colleagues have identified the enzyme responsible for the biochemical effects of nitroglycerin, and also where that enzyme does its work and why the good effects wear off.
It's a discovery that opens the way to new drugs that could have the beneficial effects of nitroglycerin without its drawbacks.
What has always been known is that the artery-widening effect is produced by nitric oxide, which is created when an enzyme breaks down nitroglycerin. The key to that reaction, says a report in tomorrow's Proceedings of the National Academy of Sciences, is an enzyme called mitochondrial aldehyde dehydrogenase (mALDH). It does its work in the mitochondria, which are cell components that convert food to energy.
"Understanding that this is this enzyme is important, but knowing that it acts in the mitochondria gives new insight into why nitroglycerin is not as successful a drug as we had hoped," Stamler says.
What happens is that the mALDH supply of the mitochondria becomes depleted after repeated exposure to nitroglycerin, the Duke researchers report. That finding explains why nitroglycerin can cause damage to heart cells, Stamler says. He describes it as an oxidizing reaction similar to the rusting of iron.
"Rust is a famous way of damaging cells," Stamler says. "It is one common mechanism for the way cells die. So there can be a great biological price for the beneficial effect of nitroglycerin."
Now the path toward better heart drugs is open, he says.
"First, we now understand at the simplest level why some drugs inhibit nitroglycerin activity," he says. "Now we can take a close look at these drug interactions. And now we have a biochemical marker for so-called nitroglycerin tolerance. Also, we have a clear way to create new molecules with nitroglycerin activity."
Stamler's group is putting their discovery to work.
?We have made some different molecules that we think should work, and that won't inhibit the enzyme in the same way," he says. "Also, we have a new class of drugs, nitrate derivatives, that we believe can be used in other parts of the body and won't have this problem."
In an accompanying commentary, Louis J. Ignarro, the 1998 Nobel laureate in medicine who is a professor of molecular and medical pharmacology at the University of California at Los Angeles, says a challenge will be to target a new drug so that it can have a full effect.
"Despite the desire to avoid tolerance, it may be a difficult task, indeed, to come up with a better anti-anginal drug than the 130-year-old nitroglycerin," Ignarro says.
What To Do
You can learn more about nitroglycerin from the Milton S. Hershey Medical Center or the Texas Heart Institute.
