Potential role of the peroxynitrite-poly(ADP-ribose) synthetase pathway in a rat model of severe hemorrhagic shock

Peroxynitrite (a potent oxidant produced by nitric oxide and superoxide) and hydroxyl radical, reactive oxidants produced during hemorrhagic shock, are potent triggers of DNA single-strand breakage. DNA injury triggers the activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS), which contributes to cellular injury. Hemorrhagic shock is associated with early vasomotor paralysis as well as with early derangements in the cellular metabolic status. Here we have tested whether activation of PARS contributes to the vasodilatation and early mortality in a rat model of severe hemorrhagic shock. In anesthetized rats hemorrhaged to a mean arterial blood pressure of 35 mmHg, pretreatment with the PARS inhibitor 5-iodo-6-amino-1,2-benzopyrone significantly improved survival rate. Furthermore, an inhibitor of nitric oxide biosynthesis (N^G-methyl-L-arginine) and the cell-permeable superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid) porphyrin also offered a significant protection in terms of hypotension and acute mortality. However, the selective inhibitor of the inducible nitric oxide synthase, mercaptoethylguanidine, failed to affect blood pressure or mortality. The present data suggest that PARS activation plays a role in the pathophysiology of hemorrhagic shock. Early production of peroxynitrite (produced by nitric oxide from constitutive nitric oxide synthase) and hydroxyl radical may induce DNA single-strand breakage, which is the immediate trigger of PARS activation.