Biochemical mechanism of nitroglycerin action and tolerance: Is this old mystery solved?

Organic nitrates such as nitroglycerin (NTG) have been used as potent vasodilators in medicine for more than a century, but their biochemical mechanisms of action, particularly in relation to tolerance development, are still incompletely defined. Numerous candidate enzymes for NTG metabolism, as well as a multiplicity of tolerance mechanisms, have been proposed in the literature, but a consolidating hypothesis that links these phenomena together has not appeared. Here, we outline a "thionitrate oxidation hypothesis," which attempts to link nitrate bioactivation and tolerance development in an overall mechanism. We also attempt to compare and contrast the proposed mechanism against existing theories of nitrate action and tolerance. Interactions between organic nitrates, which have been thought of as endothelium-independent agents, and the vascular endothelium and endothelial nitric oxide synthase (eNOS) are also discussed.