Posted on 06/04/2002 5:47:43 PM PDT by Libloather
Secrets of Heart Drug Used for Decades Revealed
Mon Jun 3, 5:32 PM ET
By Merritt McKinney
NEW YORK (Reuters Health) - Nitroglycerin has been used to relieve chest pain for more than a century, but researchers have just now discovered how the drug works. A team at the Howard Hughes Medical Institute at Duke University Medical Center in Durham, North Carolina, has discovered that an enzyme in the power plants of cells is the key to nitroglycerin's effects.
What's more, the scientists have found that long-term use of nitroglycerin slowly depletes the supply of this enzyme, which probably explains why people eventually develop a tolerance to the drug.
In an interview with Reuters Health, Dr. Jonathan S. Stamler, the lead investigator, explained that the cardiovascular benefits of nitroglycerin were discovered by chance more than 100 years ago when employees of the Swedish industrialist Alfred Nobel noticed that their chest pain diminished while working with nitroglycerin to produce dynamite. Since that time, the drug has been used to treat heart failure and a type of heart-related chest pain called angina.
Nitroglycerin is known to relieve chest pain by causing blood vessels to widen, which increases blood flow. Nitroglycerin is believed to work by being converted into a vessel-regulating substance called nitric oxide, but exactly how this happens has puzzled scientists.
Stamler and his colleagues believe that they have solved this riddle. The researchers identified an enzyme located in structures called mitochondria, which are the "powerhouses" of cells. This enzyme, called mitochondrial aldehyde dehydrogenase (mtALDH), breaks down nitroglycerin and releases a molecule related to nitric oxide, according to a report in the June 11th issue of the journal Proceedings of the National Academy of Sciences.
While nitroglycerin brings relief to people with heart disease, over time, the drug becomes less useful as patients develop a tolerance to its effects. To delay the development of this tolerance for as long as possible, doctors do not prescribe it continuously, according to Stamler.
In their experiments, the researchers believe that they have discovered why this tolerance develops. Nitroglycerin seems to lose its effects because it slowly depletes the supply of mtALDH in the mitochondria, making the enzyme less able to break down nitroglycerin.
"You're basically rusting up the system," Stamler said. The more a person takes nitroglycerin, the more the drug depletes the supply of mtALDH in mitochondria, he explained.
"Ultimately, the cell loses its power," he said.
This eventual power outage seems to explain why, despite nitroglycerin's ability to relieve chest pain in the short term, patients "may pay a price in the long term." He noted that nitroglycerin has not been shown to increase survival in people with cardiovascular disease.
The good news, according to Stamler, is that now that the basic workings of nitroglycerin are understood, it may be possible to develop more effective drugs that avoid the drawbacks of nitroglycerin. It may also be possible to counteract the "rusting" effects of nitroglycerin on the mitochondria by giving the drug in combination with other medications, he said.
In the meantime, the findings suggest other ways to improve the effectiveness of nitroglycerin in patients already taking the drug, according to the Duke researcher. He noted that some medications, including certain diabetes drugs, sleeping pills and the painkiller acetaminophen (Tylenol), also inhibit mtALDH, the enzyme that breaks down nitroglycerin. It is too early to say that patients taking nitroglycerin should avoid these medications, but if there is a suitable alternative available, it might be worth switching, Stamler said.
He added that alcohol may interfere with the effects of nitroglycerin. So, despite the cardiovascular benefits of moderate alcohol consumption, "that drink a day may not be such a good idea" for people on nitroglycerin, Stamler said.
The study "teaches us that mitochondrial aldehyde dehydrogenase is at least partially responsible for the bioactivation of nitroglycerin and is likely the target of nitroglycerin tolerance," according to Dr. Louis Ignarro at the University of California at Los Angeles.
By understanding how nitroglycerin works, it may be possible to develop new drugs with similar benefits that do not lead to the tolerance seen with nitroglycerin, he notes in an accompanying editorial.
SOURCE: Proceedings of the National Academy of Sciences 2002;99:8306-
Nitro works almost instantly--really amazing. You put a tiny pill under your tongue. In 30 sec to one minute, the chest pain eases and you get a pounding migraine headache in return.
IMDUR was worse: it gives a 24-hour pounding migraine, which, when it subsides, means you have to take another dose.
No thanks. I am glad I am now off both drugs. Incredible when needed but the side effect is nasty.
--Boris
I've always wondered this about various foods and illegal drugs. Someone was the first (probably a libertarian caveman) to try to corn shuckings and eventually stumbled on to pot. I just want to know who was the first to think to eat clams. YUCK
I think you've got the theme for a good book there.
I'd buy it.
I just had the image of a "mad" scientist in his lab, feverishly trying to develop a mutant line of "spontaneously" combusting/exploding humans who would explode on command, instead of exploding spontaneously.
Come to think of it...brainwashing the Palestinian children into becoming homicide bombers accomplishes just about the same thing.
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