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Organic Nitrates As A Theraputic Agent

2514 words - 11 pages

Introduction
Organic 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, for instance, 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 (CYPs), xanthine oxidase (XO), glutathione-S-transferases (GSTs), aldehyde dehydrogenases (ALDHs), and so on (Table 1). 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. Elevated intracellular cGMP inhibits the entry of calcium into the cell, and hence causing smooth muscle relaxation and vasodilation. Therefore, ORNs’ vasodilatory effect is coupled to their metabolism in vascular smooth muscle. NO acts predominantly on venous capacitance vessels, thereby reduces venous pressure and ventricular preload, which decrease myocardial wall tension and oxygen demand by heart (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 precursor of NO and the link between NO and activation of sGC. Investigation of these hurdles were impeded by limited tools to measure labile reaction intermediates (e.g. ORN-enzyme complex or thionitrate) and released NO (half-life of approximately 5.6 s), as well as the produced NO_x^- ions from ORN metabolism due to relatively high concentrations of these endogenous ions (Kelm and Schrader, 1990). The breakthrough came in the last decade when various methods were developed to detect and quantify these unstable reaction intermediates and products, such as nano-flow liquid chromatography mass spectrometry (nano-LC/MS) with collision-induced dissociation or electron-transfer dissociation (measurement of thionitrate intermediate), LC/MS/MS with electrospray ionization (measurement of various nitrate intermediates), and NO electrode (quantification of release NO) (Cherian et al., 2000; Miyayama et al., 2006; Krishnatry et al., 2011). Two metabolism pathways have been proposed in 1994 and are widely accepted now, mechanism-based and clearance-based metabolism of NTG (Bennett et al., 1994). The mechanism-based pathway, which produces glyceryl 1, 2-dinitrate (1, 2-GDN) as the major metabolite of NTG denitration, is associated with bioactivation of ORNs and NO generation. In contrast, clearance-based pathway yields glyceryl 1, 3-dinitrate (1, 3-GDN) and less potent vasodilator nitrite ion...

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