New insights into bioactivation and effects of organic nitrates, nitrate tolerance and cross-tolerance: a molecular approach.

A. Daiber. University Medical Center Mainz, 2. Medizinische Klinik, 55131, Germany

The hemodynamic and antiischemic effects of nitroglycerin (GTN) are lost upon chronic administration due to the rapid development of nitrate tolerance. The mechanism of this phenomenon has puzzled several generations of scientists, but recent findings have lead to novel hypotheses. The formation of reactive oxygen and nitrogen species (RONS) in the mitochondria and the subsequent inhibition of the nitrate-bioactivating enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) appear to play a central role, at least for GTN that is bioactivated by ALDH-2. Importantly, these findings provide the opportunity to reconcile the two “traditional” hypotheses of nitrate tolerance, i.e. the one postulating a decreased bioactivation and the concurrent one suggesting a role of oxidative stress. Further, recent animal and human experimental studies suggest that the organic nitrates are not a homogeneous group but demonstrate a broad diversity with regard to induction of vascular dysfunction, oxidative stress and other side-effects. In the past, attempts to avoid nitrate-induced side-effects have focused on administration schedules that would allow a ”nitrate-free interval”; in the future, the role of cotherapies with antioxidant compounds and of activation of endogeneous protective pathways such as the heme oxygenase 1 (HO-1) will need to be explored. On the other hand, the development of new nitrates, e.g. tolerance-free aminoalkyl nitrates or combination of nitrate-groups with established cardiovascular drugs like ACE inhibitors or AT1-receptor blockers (hybride molecules) may be of great clinical interest.