How is tolerance of nitrates?

Tolerance to the actions of nitrates develops rapidly for their vasodilatory effects. Tolerance to nitroglycerin in vivo is associated with reduced biotransformation ofnitrates to NO by endothelial intracellular sulfhydryl depletion as a cause oftolerance. This abnormality in nitrate biotransformation is associated with increasedmitochondrial formation of free radical oxygen species Tolerance can be overcome by providing a “daily nitrate free interval” to restoresensitivity to the drug, typically 10 to 12 hours.