IntroductionOrganic nitrates (ORN) have been used for the prevention and treatment of myocardial ischemia and angina for approximately 130 years. These are polyolesters of nitric acid (RONO2) which can be classified into two categories: very potent ORNs which contain three or four nitrate groups, such as nitroglycerin (NTG) and pentaerythritol tetranitrate (PETN); Low potency ORN 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-transferases (GST), aldehyde dehydrogenases (ALDH), etc. (Table 1). The released NO activates soluble guanylyl cyclase (sGC), which converts guanosine-5'-triphosphate (GTP) to 3',5'-cyclic guanosine monophosphate (cGMP) in vascular smooth muscle cells. High intracellular cGMP inhibits calcium entry into the cell, thereby causing smooth muscle relaxation and vasodilation. Therefore, the vasodilator effect of ORNs is coupled to their metabolism in vascular smooth muscle. NO acts primarily on venous capacitance vessels, thereby reducing venous pressure and ventricular preload, which decreases myocardial wall tension and the oxygen demand of the heart (Munzel and Gori, 2013). Although several enzymes have been identified to metabolize and bioactivate ORNs, the corresponding mechanisms remain incompletely understood, particularly with regard to the NO precursor and the link between NO and sGC activation. Studying these obstacles has been hampered by the limited number of tools for measuring labile reaction intermediates (e.g. OR ...... middle of paper ...... oic acid (Packer et al. , 1987 ; Watanabe et al., 1998b ; Gori et al., 2001 ; , prevents tolerance and minimizes cardiac damage by increasing the level of ALDH2 (Chen et al., 2008).ConclusionsOrganic nitrates have been an exogenous source of nitric oxide and an excellent therapeutic agent for various diseases for over a century. Although they act quickly and are relatively safe, chronic application of ORN induces pharmacological tolerance and endothelial dysfunction. The study of the metabolism (bioactivation and clearance) of ORN has allowed us to understand the underlying mechanisms. underlying generation, tolerance and potential toxic effects of NO, and thus to propose corresponding avoidance strategies and expand the use of this potent agent..