Different signalling pathways mediate the opposite effects of endogenous versus exogenous nitric oxide on hydroperoxide toxicity in CHP100 neuroblastoma cells

The results presented in this study indicate that the toxic response brough t about by increasing concentrations of tert-butylhydroperoxide in CHP100 c ells was mitigated significantly by exogenously added nitric oxide donors v ia a cyclic GMP-independent mechanism, In contrast with these results, endo genous nitric oxide generated by the Ca2+-mobilizing agent caffeine was fou nd to increase hydroperoxide toxicity. Under these conditions, nitric oxide was not directly toxic to the cells, Rather, nitric oxide was found to pro mote the caffeine-mediated release of Ca2+ from ryanodine-sensitive Ca2+ st ores via a cyclic GMP-independent mechanism. Release of the cation from rya nodine-sensitive Ca2+ stores was causally linked with the caffeine/nitric o xide-mediated enhancement of tert-butylhydroperoxide toxicity, It is conclu ded that endogenous and exogenous nitric oxide activate diverging signallin g pathways independent of cyclic GMP formation and causing opposite effects on the toxic response evoked by tert-butylhydroperoxide in CHP100 cells.