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.
Fung
Ho-Leung
HL
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York 14260-1200, USA. hlfung@acsu.buffalo.edu
D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004361:Drug Tolerance / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D005996:Nitroglycerin / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014665:Vasodilator Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use
D014665:Vasodilator Agents; D013481:Superoxides; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D005996:Nitroglycerin