THIOLS AND NITRATES - REEVALUATION OF THE THIOL DEPLETION THEORY OF NITRATE TOLERANCE

Organic nitrates like nitroglycerin are widely used in the treatment o f ischemic heart disease. The magnitude and duration of their circulat ory and anti-ischemic effects are, however, rapidly reduced during con tinuous treatment. Although the exact enzymatic mechanism responsible for the bioactivation of nitrates has not been defined, it is clear th at their pharmacodynamic effects depend strongly on intracellular thio l levels. Based on in vitro experiments, it was subsequently hypothesi zed that nitrate tolerance is caused by reduced bioconversion of nitra tes to nitric oxide (NO) and that depletion of intracellular thiol com pounds might be responsible for this process (the thiol depletion theo ry of nitrate tolerance). This hypothesis has, however, not been confi rmed in recent in vivo studies showing that the vascular nitroglycerin derived NO formation is similar in tissues from nontolerant and nitra te tolerant rats and that hemodynamic nitrate tolerance develops witho ut 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 sid e, exogenous thiol administration augments the hemodynamic response to nitrates. This effect is not tolerance specific and thiols, per se, a lso have the potential to affect a wide range of physiologic reactions occurring during prolonged nitrate exposure (e.g., via antioxidant ef fects or angiotensin-converting enzyme inhibition). (C) 1998 by Excerp ta Medica, Inc.