MECHANISMS INVOLVED IN THE DEVELOPMENT OF TOLERANCE TO NITROVASODILATORS

The identification of endothelium-derived relaxing factor (EDRF) as nitric oxide (NO) has highlighted the clinical importance of NO-containing drugs (nitrovasodilators and molsidomine). The development of tolerance and cross-tolerance is a well-known problem with the classic nitrovasodilators. Although counterregulatory reflex mechanisms might be involved, desensitization of the vascular smooth muscle cells is the best documented mechanism of tolerance. Impaired metabolization of organic nitrates due to deficiency of reduced thiol groups seems to be the major mechanism responsible for this vascular desensitization. Tolerance preventing strategies (nitrate-free periods, administration of N-acetylcysteine, and use of drugs that do not require thiolgroups for activation of guanylate cyclase) are based on this mechanism.