Nitrate tolerance from a biochemical point of view

Tolerance to nitrate vasodilators appears to be a general phenomenon that encompasses all known drugs belonging to this group, with the possible exception of molsidomine, for which tolerance has not yet been unambiguously proven. The mechanism behind tolerance development is still obscure, although decreased distribution of drug to the target tissue (i.e. the vascular wall) may be important. In addition, the production of cyclic guanosine-3',5'-monophosphate (cGMP) [the alleged mediator of nitrate-induced vascular smooth muscle relaxation] is reduced in tolerant tissue, while its degradation is increased. These changes could be due to a direct effect on the enzymes involved in the formation and degradation of cGMP in the cell, i.e. guanylate cyclase and phosphodiesterase, respectively. Furthermore, there is some evidence that the degradation of organic nitroesters in the vascular wall is reduced in tolerant tissue. This could result in a reduced production of unstable chemical intermediates (e.g. nitrosothiols), which have been suggested to act as mediators of guanylate cyclase.