Scientists Solve Nitroglycerin Mystery

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Scientists Solve Nitroglycerin Mystery JoAnn Guest Aug 18, 2005 15:02 PDT

 

 

 

 

August 18, 2005 01:55:34 PM PST

By Alan Mozes

HealthDay Reporter

 

 

THURSDAY, Aug. 18 (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. "

______________

JoAnn Guest

mrsjo-

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AIM Barleygreen

" Wisdom of the Past, Food of the Future "

 

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