ALDH2 Activator: The Answer to Nitroglycerine Tolerance?

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Nitroglycerine has been used for more than a century to improve myocardial function following heart failure and myocardial infarcts. However, its use is limited by the patients’ tendency to develop tolerance to its effects. Recently, it has also been found that prolonged use of nitroglycerine may result in the worsening of myocardial injury, which can even be fatal. The ALDH2 activator  may be the answer to the problem of continuous nitroglycerine use.

Nitroglycerine Effects on Heart Failure

Anatomy of a Heart Attack: Image courtesy of the US Food and Drug Administration

Over seven million people world-wide die of ischemic heart disease annually. This disease (insufficient supply of blood to the heart) often results from hypertension and high blood cholesterol, leading to heart attacks (myocardial infarction), heart failure, and subsequent death. A common drug used in the management of these conditions is nitroglycerine, or glyceryl trinitrate (GTN), often in combination with other drugs, which aim to improve myocardial performance through increased perfusion.

GTN effectively promotes vasodilatation which results in increased blood flow to the heart. It also decreases myocardial wall stress by dilating systemic veins, thus restoring the balance of oxygen and nutrient supply and demand in the ischemic heart.  The vasodilator effects of GTN were discovered to be mediated by nitric oxide (NO). These positive effects, however, are limited by tolerance after several hours of continuous administration.

Tolerance to Nitroglycerine Treatment

Nitroglycerin tolerance is partly caused by the inactivation of aldehyde dehydrogenase 2 (ALDH2), an enzyme that converts GTN to nitric oxide. Researchers Julio C.B. Ferreira, PhD, and Daria Mochly-Rosen, PhD, of the Stanford University School of Medicine, Stanford, CA, recently found that in animal models, in addition to GTN’s effect on the blood vessels, sustained treatment negatively affected the heart muscle cells’ viability following ischemia, resulting in the increased size of infarcts (damaged portions of the heart).

In 2008, Mochly-Rosen and colleagues found that ALDH2 is a critical enzyme for protecting the heart from damage caused by ischemia not just for people being treated with nitroglycerin, but for everyone. After reaching this conclusion, the researchers became concerned about the safety of sustained nitroglycerin use.

The Role of ALDH2 Activator

Dr. Daria Mochly-Rosen Image courtesy of Stanford

In their 2011 study entitled, “ALDH2 Activator Inhibits Increased Myocardial Infarction Injury by Nitroglycerin Tolerance,” Mochly-Rosen showed that the damage caused by nitroglycerine can be reduced by simultaneous treatment with an enzyme activator known as Alda-1. When the treated rats were given the enzyme activator Alda-1 along with nitroglycerin, the detrimental effects of prolonged nitroglycerin treatment were nearly obliterated.

Alda-1 prevented the nitroglycerin-induced increase in cardiac injury after myocardial infarction in the rats by enhancing metabolism of reactive aldehyde adducts that impair normal protein functions. If the animal studies are corroborated in humans, activators of ALDH2 such as Alda-1 may help to protect patients with myocardial infarction from nitroglycerin-induced spread in cardiac injury while maintaining the vasodilator effects of nitric oxide produced by GTN.

The Future of ALDH2 Activator in Heart Disease Treatment

ALDH2 can prevent damage due to sustained nitroglycerine use: Image by Ayacop

While the potential of finding a drug that can counteract nitroglycerine tolerance and its negative effects is on its way, Dr. Daria Mochly-Rosen says that ALDH activators have not yet been tested in humans. In an exclusive interview with Decoded Science, she explains, “The next step is formal toxicity studies in animals, followed by a request from the FDA for permission to do clinical trials in humans (this request is called IND = Investigative New Drug application). A company, called ALDEA (which I co-founded) is working on this last stage of drug development with the hope to start human trials in the next year and a half.”

No complications of using aldehyde dehydrogenase activators in mice have been observed, but potential complications still need to be examined in human studies.

References

Lihan Sun, Julio Cesar Batista Ferreira, Daria Mochly-Rosen. ALDH2 Activator Inhibits Increased Myocardial Infarction Injury by Nitroglycerin ToleranceScience Translational Medicine. (2011) 3 (107): 107ra111 DOI: 10.1126/scitranslmed.3002067. Accessed December 13, 2011.

Julio Cesar Batista Ferreira, Daria Mochly-Rosen. Nitroglycerin Use in Myocardial Infarction Patients – Risks and Benefits. Circulation Journal. (2011). Accessed December 13, 2011.

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