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Figure 1 The Scheme Depicts Proposed Pathways of Organic Nitrate Bioactivation in Vascular Cells
The left part characterizes the bioactivation of high potency nitrates such as nitroglycerin (GTN), pentaerythrityl tetranitrate (PETN), and pentaerythrityl trinitrate (PETriN) by mitochondrial aldehyde dehydrogenase (ALDH-2), when employed at clinically relevant concentrations (<1 µM). The reductase activity converts the organic nitrates to nitrite and the denitrated metabolite (1,2-glyceryl dinitrate [GDN], PETriN or its dinitrate PEDN). Nitrite in turn requires further bioactivation by either reduction by the respiratory chain (cytochrome oxidase [cyt ox]) or acidic disproportionation in the inner membrane space, finally yielding nitric oxide (NO) or a related species (NOx), which is able to activate soluble guanylyl cyclase. The resulting increase in cyclic guanosine monophosphate (cGMP) will activate the cGMP-dependent kinase I, which in turn causes vasodilatation via several mechanisms. The right portion depicts the bioactivation of low-potency nitrates such as isosorbide dinitrate (ISDN) and isosorbide-5-mononitrate (ISMN) but also GDN, PEDN, and their respective mononitrates, glyceryl (GMN) and pentaerythytyl mononitrate (PEMN), by P450 enzyme(s) in the endoplasmic reticulum (ER) directly yielding. The latter mechanism also accounts for the high-potency nitrates, when employed at high concentrations (>1 µM). Reprinted with permission from Munzel et al. (11). sGC = soluble guanylate cyclase.
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