Nitric oxide, peroxynitrite and poly (adpribose) synthetase activation: role in the suppression of cellular energetics

Our current results demonstrate that peroxynitrite, a cytotoxic oxidant, induces DNA strand-breakage, which activates the nuclear enzyme poly (ADP-ribose) synthetase (PARS) and initiates an energy consuming, inefficient repair cycle, which leads to cellular dysfunction (Szabó, Free Rad Biol Med, 21: 855, '96). While peroxynitrite-induced cellular energetic changes (suppression of mitochondrial respiration, decrease in NAD⁺, and decrease in cellular ATP) were ameliorated by inhibition of the activity of PARS, the cellular energetic derangement by "pure" NO (in the absence of superoxide generators) was not prevented by inhibition of PARS. These findings are in agreement with data showing that peroxynitrite, but not NO per se, initiates DNA single strand breakage. At high peroxynitrite concentrations, the protection provided by PARS inhibition wanes. Thus, there are distinct NO- and peroxynitrite- induced pathways of metabolic inhibition, the former one being PARS-independent, while the latter one involving both PARS-dependent PARS-independent components. In addition to the in vitro data, in vivo data will also be presented to show peroxynitrite production and protection by PARS inhibition against the tissue injury during ischemia-reperfusion and in inflammation.