Scientists Solve Nitroglycerin Mystery

They now know how it helps the heart, but can it cause harm, too?

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By Alan Mozes
HealthDay Reporter

THURSDAY, Aug. 18, 2005 (HealthDay News) -- The 150-year-old riddle of what makes nitroglycerin work as a cardiovascular treatment appears to have been solved by a team of American and Japanese scientists.

But the answer also raises important questions about the safety of the drug as a treatment for chest pain.

In fact, the researchers now advise that, until further studies are conducted, nitroglycerin should be prescribed only in moderation, and not at all to patients already taking a large number of other medications.

"You take it for granted that when a drug is given that we know what we're doing, and that has not been the case for nitroglycerin," said study co-author Dr. Jonathan S. Stamler, of the department of medicine and the Howard Hughes Medical Institute at Duke University Medical Center. "We now finally understand how this drug works for the first time, and that the drug may not be useful in many of the forms it is now given."

Nitroglycerin is one of the oldest cardiovascular drugs -- in continuous use by doctors since 1847. Its benefits for the relief of chest pain were first observed in the Swedish explosives factory of Alfred Nobel -- founder of the Nobel Peace Prize -- where the compound was a key ingredient in dynamite.

The invention helped make Nobel a rich man, with the added bonus of making some of his workers feel better while on the job. Eventually, nitroglycerine's blood vessel-dilating properties became clear, even though the mechanism driving this effect remained murky. The medication ultimately became one of the mainstays of cardiac treatment, but in the absence of the kind of rigorous scientific scrutiny new drugs receive today.

Seeking to shed light on the drug's mechanics, Stamler and his colleagues report in this week's online issue of the Proceedings of the National Academy of Sciences on their work with two groups of mice: one normal and one genetically altered.

The altered mice lacked a specific enzyme, called mtALDH, that's present normally within the cell's 'energy factories,' the mitochondria.

When nitroglycerin was given to the normal mice -- in doses comparable to those given to human patients -- the researchers witnessed a drop in blood pressure that would normally be expected after drug application.

However, when nitroglycerin was given to the mice lacking mtALDH, the drug had no effect on blood pressure.

Based on this result, the team concluded that the mtALDH enzyme is key to nitroglycerin's ability to lower blood pressure.

They explain that mtALDH initiates the breakdown of nitroglycerin into nitric oxide, a 'vasodilator' that opens up blood vessels and lowers blood pressure. Nitric oxide has an important regulatory role in blood vessel dilation, and is normally present in the bloodstream.

But solving the nitroglycerin puzzle may bring a new set of problems.

For one, the interaction between nitroglycerin and certain classes of prescribed medications could cause trouble, the researchers note.

Drugs such as sulfonylureas, used by diabetics; and chloral hydrates, used by patients with sleep disorders; tend to lower mitochondrial enzyme activity and may thereby reduce the effectiveness of nitroglycerin. Even the common use of alcohol or acetaminophen (such as Tylenol) can have a similar effect.

In addition, patients whose mitochondrial enzymes are generally less active -- a genetic condition found most commonly among certain Asian populations -- might not respond well to nitroglycerin, they said.

Finally, Stamler's group worry that cardiac patients using the drug on a long-term basis might, in fact, be damaging their mitochondria over time.

This effect may account for the long-observed drop in nitroglycerin's ability to lower blood pressure when used over the long term.

More seriously, Stamler said, such damage may also lead to a worsening of overall cardiovascular condition -- in effect, rusting out heart cells through oxidation.

Diabetics are at a particular risk for these types of cardiovascular complications due to nitroglycerin use since they typically experience mitochondrial damage even before taking the drug.

"It's really quite an amazing thing," said Stamler. "Nitroglycerin has a very romantic association with science and scientific endeavor. But there is good reason to believe the drug may not be efficacious and might even be dangerous. It's perhaps interesting to point out that Alfred Nobel himself suffered from heart disease, but even he refused to take nitroglycerin -- thinking that no one in his right mind would take an explosive."

"People can be very concerned -- and I am very concerned," added Stamler --cautioning that nitroglycerin's worth as a treatment option can only be validated by large-scale studies.

Dr. David A. Kass, a professor of medicine and biomedical engineering at Johns Hopkins Medical Institutions in Baltimore, countered that while further studies are never a bad idea he sees no evidence to suggest that anyone taking nitroglycerin should be alarmed.

"It's not that we've identified something that's very troubling and disturbing, or that people are dying," he said. "I don't think there's any meaningful data to suggest that nitrates taken chronically, in fact, kill you. There's certainly data to suggest that nitrates taken chronically are ineffective. And this study has described a new mechanism for why you might lose this effectiveness. But whether this leaves you more vulnerable or not I think is very speculative."

More information

For more on nitroglycerin, check out the Texas Heart Institute.

SOURCES: Jonathan S. Stamler, M.D., department of medicine and Howard Hughes Medical Institute, Duke University Medical Center, Durham, N.C.; David A. Kass, M.D., professor, medicine and biomedical engineering, Johns Hopkins Medical Institutions, Baltimore; Aug. 15-19, 2005, Proceedings of the National Academy of Sciences online

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