IntroductionOrganic nitrates (ORNs) have been used for the prevention and treatment of myocardial ischemia and angina pectoris for approximately 130 years. They are polyolesters of nitric acid (RONO2) that can be classified into two categories: high-potency ORNs that contain three or four nitrate groups, such as nitroglycerin (NTG) and pentaerythritol tetranitrate (PETN); Low potency ORNs containing one or two nitrate groups, e.g. isosorbide dinitrate (ISDN), isosorbide-2-mononitrate (IS-2-MN), isosorbide-5-mononitrate (IS-5-MN), and nicorandil (Munzel et al ., 2005). ORNs are bioactivated to produce nitric oxide (NO) by various enzymes, including cytochrome P450 (CYP), xanthine oxidase (XO), glutathione-S-transferase (GST), aldehyde dehydrogenase (ALDH) and so on (Table 1). The released NO activates soluble guanylyl cyclase (sGC), which converts guanosine-5'-triphosphate (GTP) to cyclic guanosine monophosphate 3',5' (cGMP) in vascular smooth muscle cells. Elevated intracellular cGMP inhibits calcium entry into the cell, thereby causing smooth muscle relaxation and vasodilation. Therefore, the vasodilatory effect of ORNs is coupled to their metabolism in vascular smooth muscle. NO acts predominantly on capacitive venous vessels, thus reducing venous pressure and ventricular preload, which reduce myocardial wall tension and cardiac oxygen demand (Munzel and Gori, 2013). Although several enzymes have been identified to metabolize and bioactivate ORNs, the corresponding mechanisms still remain incompletely understood, especially regarding the NO precursor and the link between NO and sGC activation. Investigation of these obstacles has been hampered by limited tools for measuring labile intermediates of the reaction (e.g. OR...... middle of paper ......oic acid (Packer et al., 1987; Watanabe et al., 1998b; Watanabe et al., 1998a; Gori et al., 2001; Dudek et al., 2008). Furthermore, the inducer of ALDH2, ALDA-1, has been shown to prevent tolerance and minimize damage cardiac by increasing the level of ALDH2 (Chen et al. , 2008). Conclusions Organic nitrates have been used as an exogenous source of nitric oxide and as an excellent therapeutic agent for various cardiovascular diseases for more than a century are relatively safe, chronic application of ORNs induces pharmacological tolerance and endothelial dysfunction. The study of the metabolism (bioactivation and elimination) of ORNs has allowed us to understand the mechanisms underlying NO generation, tolerance and potential toxic effects, and therefore to provide corresponding avoidance strategies and extend the use of this powerful agent..