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Figure 2 The Mechanism of the Dichotomous Biological Effects of Nitrates
When administered acutely, nitroglycerin is biotransformed in the mitochondrial matrix by the aldehyde dehydrogenase (ALDH) to release a nitric oxide–related species (NOx). At the same time, nitroglycerin causes uncoupling of the mitochondrial respiratory chain and a burst of oxygen free radicals (ROS). Acutely, nitroglycerin activates a cascade that results in a phenotypic protection that is similar to ischemic preconditioning. The sudden increased bioavailability of nitric oxide and oxygen free radicals seems to have a critical role in the cascade that leads to nitrate preconditioning. Of note, isosorbide mononitrate, which has an extramitochondrial bioactivation (and ROS production), does not cause preconditioning (23). On chronic administration, nitrate-induced ROS production causes a number of adverse effects, which include rebound ischemia, endothelial and autonomic dysfunction, and oxidation of a critical thiol group in the active site of ALDH, resulting in impaired nitrate biotransformation and nitrate tolerance. GTN = nitroglycerin; ISMN = isosorbide mononitrate.
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