Imagine being treated with a commonly prescribed drug that works in ways of which physicians have no knowledge.
Sound far-fetched? Maybe not--for over 130 years, doctors have treated heart disease patients with nitrate-containing compounds such as nitroglycerin without any understanding of how they actually worked. Worse still, many patients develop tolerance to the drugs within a matter of hours, prompting changes to treatment methods and questions about why this was happening.
For the first time, Medical Center researchers identified the mechanisms that control nitroglycerin's biological activity. In a paper published in the Proceedings of the National Academy of Sciences last week, the scientists also hypothesize how tolerance to the treatment develops and suggest that in the end nitroglycerin may not provide any help to patients.
"There is nothing in the literature that says a patient will benefit from [nitroglycerin]. In fact, there are studies suggesting it may have adverse effects," said lead investigator Dr. Jonathan Stamler, professor of pulmonary medicine. "Nitrates have been a mainstay of therapy for [cardiovascular problems for] 130 years and is the most often used drug to treat common heart disease. I find it rather remarkable we gave it without knowing how it works."
Following heart complications, patients need nitric oxide, a cardioprotective agent, in their bodies to help relax blood vessels. For some time, it was believed that nitroglycerin could provide nitric oxide but it was unclear how. Using a macrophage model and a more specific protocol than performed previously, the researchers were able to highlight the enzyme involved in this process and to their surprise, that it was occurring in the mitochondria.
The enzyme, called mitochondrial aldehyde dehydrogenase, or mALDH, breaks down nitroglycerin into nitric oxide. Following this activation, though, the enzyme becomes oxidized, rendering it incapable of functioning properly. As a result, the drug becomes ineffective as damaged mALDH accumulates, and the body needs time to generate new mALDH.
Furthermore, the paper includes evidence that this enzyme is broadly implicated in vascular biology.
However, the paper also suggests nitroglycerin may not be providing any benefits to patients. For example, the drug in vitro did not produce nitric oxide as expected.
Although these findings answer questions about nitroglycerin's breakdown, future research will still be needed. In addition to seeing if nitroglycerin is even necessary, scientists still do not know how the biological activity produced from nitroglycerin is used. Also, this research could be used to improve nitroglycerin's efficacy, reduce tolerance, understand any dose-dependent relationships and support development of other drugs to treat cardiovascular disease that does not have these problems.
"These findings help us understand the phenomenon of [nitroglycerin] tolerance," said Dr. Josh Hare, associate professor of medicine at the Johns Hopkins University. "This work takes several major steps forward in developing a better understanding and protocol for [heart disease] patients in the future."
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