NITRIC-OXIDE PROTECTS AGAINST ALKYL PEROXIDE-MEDIATED CYTOTOXICITY - FURTHER INSIGHTS INTO THE ROLE NITRIC-OXIDE PLAYS IN OXIDATIVE STRESS

Endogenously formed nitric oxide (NO) possesses diverse properties suc h as regulating physiological functions, exerting specific toxic effec ts, and protecting against various toxic substances. Recent studies su ggest that in the presence of reactive oxygen species, NO can serve as an antioxidant. We show here that NO delivered from the NO donor comp ound, PAPA/NO (NH2(C3H6) (N[N(O)NO](C3H7)), protects Chinese hamster V 79 lung fibroblasts from the cytotoxicity of t-butyl hydroperoxide and cumene hydroperoxide. In contrast, the other end products of PAPA/NO degradation in aqueous solution, NH2(C3H6)NH(C3H7) and nitrite, did no t protect. The NONOate DEA/NO releases NO six times faster than PAPA/N O, yet did not afford protection, which implies that NO must be presen t throughout the alkyl hydroperoxide exposure. Measurements of NO conc entrations released from PAPA/NO suggest that micromolar levels protec t against cytotoxicity induced by alkyl hydroperoxides. These findings demonstrate that the flux of NO sustained over the duration of the pe roxide exposure determines protection and not the total of NO delivere d. These results suggest that concentrations of NO produced in the mic roenvironment of endothelial cells are high enough to protect cells fr om Fenton-type-mediated toxicity and support the premise that NO may e xert a salutary effect in certain diseases associated with membrane da mage. (C) 1995 Academic Press, Inc.