Biotransformation to nitric oxide of organic nitrates in comparison to other nitrovasodilators

Abstract

Nitrovasodilators are prodrugs which, although chemically heterogenous, exert their pharmacodynamic action via a common pathway, i.e. the release of nitric oxide (NO). The NO, which results from metabolism of nitrovasodilators in vascular and non-vascular cells, stimulates the cytosolic enzyme guanylyl cyclase leading to an increase in the concentration of intracellular cyclic guanosine monophosphate (cGMP). In general, the rate of NO generation from the individual compounds correlates well with the extent of cGMP increase and their potency to relax vascular tissue. The amounts of NO generated are sufficient to inhibit platelet aggregation and to induce disaggregation. Nitrovasodilators thus mimic the action of endothelium-derived relaxing factor (EDRF). After more than a century of empiric use, the application of nitrovasodilators today may be regarded as causal therapy, since these drugs act by substituting an endogenous factor, the production or release of which is impaired under pathophysiological circumstances associated with endothelial dysfunction. Marked differences exist between individual compound classes with regard to bioactivation mechanisms, cofactor requirements, and the extent and nature of the concomittant formation of metabolites other than NO. This review describes the discovery of the mode of action of nitrovasodilators and our current understanding of the pathways involved in their bioactivation and biodegradation with special emphasis on the enzymatic and non-enzymatic metabolism of organic nitrates. In addition, the in-vivo metabolism of NO is reviewed briefly.