ALDH2 Activator Inhibits Increased Myocardial Infarction Injury by Nitroglycerin Tolerance

Tolerance to nitroglycerin, a drug often used to treat chest pain, increases susceptibility to injury by myocardial infarction. Damping the Dynamite in Nitroglycerin As a component of dynamite, nitroglycerin’s job is to destroy. As a commonly used drug, this vasodilation-inducing agent is profoundly healing and is often prescribed to alleviate angina—chest pain that arises from arteries narrowed by cardiovascular disease. Now, Sun et al. show that this drug’s destructive nature may rear its ugly head in when used to treat patients with acute myocardial infarction. In rats, continuous treatment with nitroglycerin for 16 hours before a myocardial infarction increased cardiac damage and diminished cardiac function. These detrimental effects of nitroglycerin resulted from ischemia-induced aldehydic adduct formation, likely because nitroglycerin inhibits ALDH2, a key enzyme that clears these toxic aldehydes. The nitroglycerin-induced heart pathology in the rats was inhibited when the drug was administered with Alda-1, which activates ALDH2. Another drug used to treat angina, isosorbide dinitrate, which does not modulate ALDH2 function, shows no exacerbation of the damage caused by a myocardial infarction. Ultimately, controlled clinical trials will determine the net benefit of nitroglycerin and test whether these findings from animal studies apply in humans. If they do, clinicians may want to reconsider the use of prolonged nitroglycerin treatment in patients likely to experience a myocardial infarction. Alternatively, the addition of ALDH2 activators such as Alda-1 to nitroglycerin regimens could protect patients against these negative effects of nitroglycerin, while preserving its healing benefits. Nitroglycerin, which treats impaired cardiac function through vasodilation as it is converted to nitric oxide, is used worldwide for patients with various ischemic and congestive cardiac diseases, including angina pectoris. Nevertheless, after continuous treatment, the benefits of nitroglycerin are limited by the development of tolerance to the drug. Nitroglycerin tolerance is a result of inactivation of aldehyde dehydrogenase 2 (ALDH2), an enzyme essential for cardioprotection in animals subjected to myocardial infarction. Here, we tested the hypothesis that the tolerance that develops as a result of sustained nitroglycerin treatment increases cardiac injury by subsequent myocardial infarction. In a rat model of myocardial infarction, 16 hours of prior, sustained nitroglycerin treatment resulted in infarcts that were twice as large as those in untreated control animals and in diminished cardiac function at 3 days and 2 weeks after the myocardial infarction. We also sought to identify a potential treatment to protect against this increased cardiac damage. Nitroglycerin inhibited ALDH2 activity in vitro, an effect that was blocked by Alda-1, an activator of ALDH2. Co-administration of Alda-1 with the nitroglycerin prevented the nitroglycerin-induced increase in cardiac dysfunction after myocardial infarction in rats, at least in part by enhancing metabolism of reactive aldehyde adducts that impair normal protein functions. If our animal studies showing that nitroglycerin tolerance increases cardiac injury upon ischemic insult are corroborated in humans, activators of ALDH2 such as Alda-1 may help to protect patients with myocardial infarction from this nitroglycerin-induced increase in cardiac injury while maintaining the cardiac benefits of the increased nitric oxide concentrations produced by nitroglycerin.