Reaction of organic nitrate esters and S-nitrosothiols with reduced flavins: A possible mechanism of bioactivation

Organic nitrate esters, such as glyceryl trinitrate and isosorbide dinitrat e, are a class of compounds used to treat a variety of vascular ailments. T heir effectiveness relies on their ability to be bioactivated to nitric oxi de (NO) which, in turn, relaxes vascular smooth muscle. Although there have been many biological studies that indicate that NO can be formed from orga nic nitrate esters in a biological environment, the chemical mechanism by w hich this occurs has yet to be established. Previous studies have implicate d both flavins and thiols in organic nitrate ester bioactivation, Thus, we examined the chemical interactions of flavins and thiols with organic nitra te esters as a means of determining the role these species may play in NO p roduction. Based on these studies we concluded that a reasonable chemical m echanism for organic nitrate ester bioactivation involves reduction to the organic nitrite ester followed by conversion to a nitrosothiol, The release of NO from nitrosothiols can occur via a variety of processes including re action with dihydroflavins and NADH.