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Popular Drug for Chest Pain May Promote Blood Vessel Damage

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Duke Health News 919-660-1306

DURHAM, NC -- Nitroglycerin -- a drug commonly prescribed
for the treatment of chest pain in patients with heart
conditions -- has the frustrating property that its beneficial
effects are short-lived. Now, new research conducted by a
German group and Howard Hughes Medical Institute investigators
at Duke University Medical Center reveals the cellular
mechanism underlying the drug's lost efficacy and raises
additional concern about its potential to cause long-term
injury.

In rats treated with nitroglycerin for a period of three
days, the activity of a key enzyme in the cellular
"powerhouses" known as mitochondira declined, the research team
reported in the Feb. 1, 2004, issue of the Journal of Clinical Investigation.
Earlier studies have suggested that the enzyme, mitochondrial
aldehyde dehydrogenase (ALDH-2), is central to nitroglycerin's
ability to dilate blood vessels and boost blood flow, thereby
easing chest pain.

What's more, the research team found, mitochondria lacking
the enzyme activity due to prolonged use of the heart drug
began producing free radicals -- unstable molecules that can
damage heart cells and blood vessel walls. Such cellular damage
has been linked to further heart disease and suggests that use
of the drug may lead to increases in mortality, said Jonathan
Stamler, M.D., HHMI investigator and professor of pulmonary and
critical care medicine at Duke.

"Nitroglycerin is one of the most commonly used drugs in the
western world," Stamler said. "Our findings raise concern that
the drug may have deleterious consequences. The drug's
long-term effects on patients should be re-examined in clinical
trials and, in the meantime, physicians should use caution and
lower the dose prescribed to patients."

The broad cellular damage caused by nitroglycerin might also
explain why, in addition to nitroglycerin tolerance, patients
receiving the drug for sustained periods sometimes become
unresponsive to other heart drugs as well, the team
reported.

Rats treated with nitroglycerin for a period of three days
demonstrated tolerance to the drug, as indicated by a failure
of nitroglycerin to decrease blood pressure by dilating blood
vessels. The nitroglycerin-tolerant rats exhibited a
significant decline in activity of mitochondrial ALDH-2, the
enzyme critical to nitroglycerin's beneficial effects, relative
to control animals, the researchers reported. Therefore,
treatment of tolerant blood vessels with other substances known
to block ALDH-2 activity had little effect.

As ALDH-2 declined with nitroglycerin treatment,
mitochondria in the heart cells of rats greatly increased the
production of free radicals over control animals, the team
found. Treatment with antioxidants reduced the production of
free radicals by mitochondria and restored activity of the
ALDH-2 enzyme.

While nitroglycerin alleviates acute symptoms of heart
disease, Stamler said, the current study suggests that cellular
damage inflicted by chronic use of the drug might ultimately
increase patients' cardiovascular risk. Therefore, the drug
should be prescribed judiciously, he said. In particular,
patients with mitochondrial damage due to other medical
conditions, such as diabetes, should be treated with extra
caution, he said.

The Duke team's ongoing research will focus on possible drug
alternatives to nitroglycerin, Stamler said. The researchers
are also examining additional compounds that might block the
drug's deleterious effects while maintaining its ability to
treat heart patients.

The research team included Zhiqlang Chen of Duke; Thomas
Munzel, Karsten Sydow, Andreas Daiber, Matthias Oelze, Michael
August and Maria Wendt of The University Hospital Eppendorf in
Hamburg, Germany; Volkerr Ullrich of University Konstanz in
Konstanz, Germany; Alexander Mulsch of the University of
Frankfurt in Germany; Eberhard Schulz and John Keaney Jr. of
Boston University School of Medicine. The work was supported
with funds from the Deutsche Forschungsgemeinschaft Mu.

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