Nitric oxide protects against cellular damage and cytotoxicity from reactive oxygen species.

TLDR

Nitric oxide, produced by immune cells, is traditionally viewed as cytotoxic yet has been suggested to protect against ischemia‑reperfusion injury, and its effects are often considered synergistic with superoxide/hydrogen peroxide. The study aimed to investigate the potential synergy between nitric oxide and reactive oxygen species in mammalian cell cytotoxicity. Researchers exposed Chinese hamster lung fibroblasts and rat mesencephalic dopaminergic cells to hypoxanthine/xanthine oxidase or hydrogen peroxide, while generating nitric oxide via NONOate compounds that release NO at ambient temperature. Nitric oxide released from DEA/NO markedly reduced the dose‑dependent cytotoxicity and dopamine uptake degradation induced by superoxide or hydrogen peroxide in both V79 fibroblasts and primary dopaminergic cultures.

Abstract

Nitric oxide, NO, which is generated by various components of the immune system, has been presumed to be cytotoxic. However, NO has been proposed to be protective against cellular damage resulting during ischemia reperfusion. Along with NO there is often concomitant formation of superoxide/hydrogen peroxide, and hence a synergistic relationship between the cytotoxic effects of nitric oxide and these active oxygen species is frequently assumed. To study more carefully the potential synergy between NO and active oxygen species in mammalian cell cytotoxicity, we utilized either hypoxanthine/xanthine cell cytotoxicity, we utilized either hypoxanthine/xanthine oxidase (a system that generates superoxide/hydrogen peroxide) or hydrogen peroxide itself. NO generation was accomplished by the use of a class of compounds known as "NONOates," which release NO at ambient temperatures without the requirement of enzyme activation or biotransformation. When Chinese hamster lung fibroblasts (V79 cells) were exposed to hypoxanthine/xanthine oxidase for various times or increasing amounts of hydrogen peroxide, there was a dose-dependent decrease in survival of V79 cells as measured by clonogenic assays. However, in the presence of NO released from (C2H5)2N[N(O)NO]-Na+ (DEA/NO), the cytotoxicity resulting from superoxide or hydrogen peroxide was markedly abrogated. Similarly, primary cultures of rat mesencephalic dopaminergic cells exposed either to hydrogen peroxide or to hypoxanthine/xanthine oxidase resulted in the degradation of the dopamine uptake and release mechanism. As was observed in the case of the V79 cells, the presence of NO essentially abrogated this peroxide-mediated cytotoxic effect on mesencephalic cells.