The Na(+)/Ca(2+) exchanger (NCX) plays a role in the regulation of intracellular 
Ca(2+) levels, and nitric oxide (NO) is involved in many pathological conditions 
including neurodegenerative disorders. We have previously found that sodium 
nitroprusside (SNP), an NO donor, causes apoptotic-like cell death in cultured 
glial cells via NCX-mediated pathways and the mechanism for NO-induced 
cytotoxicity is cell type-dependent. The present study examined using the 
specific NCX inhibitor 
2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) whether NCX 
is involved in NO-induced injury in cultured neuronal cells. The treatment of 
neuroblastoma SH-SY5Y cells with SNP resulted in apoptosis and the cytotoxicity 
was blocked by the mitogen-activated protein (MAP)/extracellular 
signal-regulated kinase (ERK) kinase inhibitor U0126 and the p38 MAP kinase 
(MAPK) inhibitor SB203580, but not by the c-Jun N-terminal kinase (JNK) 
inhibitor SP60012. SNP increased Ca(2+) influx and intracellular Ca(2+) levels. 
In addition, SNP increased ERK and p38 MAPK phosphorylation, and production of 
reactive oxygen species (ROS) in an extracellular Ca(2+)-dependent manner. These 
effects of SNP were prevented by SEA0400. SNP-induced cytotoxicity was not 
affected by inhibitors of the Ca(2+), Na(+) and store-operated/capacitative 
channels. Moreover, SNP-induced increase in intracellular Ca(2+) levels, ROS 
production and decrease in cell viability were blocked by a cGMP-dependent 
protein kinase (PKG) inhibitor. These results suggest that Ca(2+) influx via the 
reverse of NCX is involved in the cascade of NO-induced neuronal apoptosis and 
NO activates the NCX through guanylate cyclase/PKG pathway.