Posted on 02/07/2004 8:49:12 AM PST by blam
Source: Duke University Medical Center
Date: 2004-02-06
Popular Drug For Chest Pain May Promote Blood Vessel Damage
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.
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The research team included Zhiqiang 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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