THE EFFECT OF VARIOUS NITRIC OXIDE-DONOR AGENTS ON HYDROGEN PEROXIDE-MEDIATED TOXICITY - A DIRECT CORRELATION BETWEEN NITRIC-OXIDE FORMATION AND PROTECTION

The role that nitric oxide (NO) plays in various degenerative and dise ase states has remained a mystery since its discovery as a biological messenger, prompting the question, ''NO, friend or foe?'' Some reports have suggested that NO is cytotoxic, and yet others have shown that i t possesses protective properties against reactive oxygen species (ROS ). Many studies have used various NO donor complexes arriving at seemi ngly different conclusions. This report will address the effects of va rious NO donor compounds on ROS-mediated toxicity. Consistent with our previous study, the NO donor compound, DEA/NO ((C2H5)(2)N[N(O)NO]Na-- +), afforded protection against hydrogen peroxide-mediated cytotoxicit y in V79 Chinese hamster lung fibroblasts at concentrations as low as 10 mu M DEA/NO. Furthermore, a survey of other NO donor complexes reve aled that some either protected or potentiated hydrogen peroxide-media ted cytotoxicity. 3-Morpholinosynodiomine(.)HCl (SIN-1) and sodium nit roprusside (SNP) enhanced hydrogen peroxide-mediated cytotoxicity, whi le S-nitrosoglutathione (GSNO), and S-nitroso-N-acetylpenicillamine (S NAP) afforded protection. Electrochemical detection of NO in cell cult ure medium revealed that neither 1000 mu M SIN-1 nor SNP yielded appre ciable NO concentrations (<0.3 mu M). In contrast, DEA/NO, SNAP, and G SNO yielded fluxes of NO >1.0 mu M. Thus, a direct correlation between inhibition of hydrogen peroxide cytotoxicity and NO production was ob served: agents that release NO during hydrogen peroxide treatment affo rd significant protection, whereas agents that do not release NO do no t protect. Similar results were observed for NO donors studied when hy poxanthine/xanthine oxidase was used as the source for ROS, although t he S-nitrosothiol agents were much less protective. These results demo nstrate that NO possesses properties which protect against ROS toxicit y and demonstrate how the use of different NO donor compounds can lead to different conclusions about the role that NO can play in the cytot oxicity of ROS. (C) 1996 Academic Press, Inc.