Thiols and nitrates: Reevaluation of the thiol depletion theory of nitrate tolerance

Organic nitrates like nitroglycerin are widely used in the treatment of ischemic heart disease. The magnitude and duration of their circulatory and anti-ischemic effects are, however, rapidly reduced during continuous treatment. Although the exact enzymatic mechanism responsible for the bioactivation of nitrates has not been defined, it is clear that their pharmacodynamic effects depend strongly on intracellular thiol levels. Based on in vitro experiments, it was subsequently hypothesized that nitrate tolerance is caused by reduced bioconversion of nitrates to nitric oxide (NO) and that depletion of intracellular thiol compounds might be responsible for this process (the thiol depletion theory of nitrate tolerance). This hypothesis has, however, not been confirmed in recent in vivo studies showing that the vascular nitroglycerin derived NO formation is similar in tissues from nontolerant and nitrate tolerant rats and that hemodynamic nitrate tolerance develops without any indication of thiol depletion, Thus, reduced biologic activity of NO, rather than thiol-mediated reduced bioconversion of nitrates to NO, may contribute to in vivo tolerance development, On the other side, exogenous thiol administration augments the hemodynamic response to nitrates. This effect is not tolerance specific and thiols, per se, also have the potential to affect a wide range of physiologic reactions occurring during prolonged nitrate exposure (e.g., via antioxidant effects or angiotensin-converting enzyme inhibition). (C) 1998 by Excerpta Medica, Inc.