Mechanism of Action
GTN is a prodrug which must first be denitrated to produce the active metabolite nitric oxide (NO). Nitrates which undergo denitration within the body to produce NO are called nitrovasodilators and their denitration occurs via a variety of mechanisms. The mechanism by which nitrates produce NO is widely disputed. Some believe that nitrates produce NO by reacting with sulfhydryl groups, while others believe that enzymes such as glutathione S-transferases, cytochrome P450 (CYP), and xanthine oxidoreductase are the primary source of GTN bioactivation. In recent years a great deal of evidence has been produced that supports the belief that clinically relevant denitration of GTN to produce 1,2-glyceryl dinitrate (GDN) and NO is catalysed by mitochondrial aldehyde dehydrogenase (mtALDH). NO is a potent activator of guanylyl cyclase (GC) by heme-dependent mechanisms; this activation results in cGMP formation from cyclic guanosine triphosphate (cGTP). Thus, NO increases the level of cGMP within the cell. cGMP then activates myosin light chain phosphatase via a cGMP-dependent protein kinase.
Read more about this topic: Glyceryl Trinitrate (pharmacology)
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