Nitric oxide (NO) is involved in many pathological conditions including 
neurodegenerative disorders. We have previously found that sodium nitroprusside 
(SNP), an NO donor, stimulates mitogen-activated protein kinases (MAPKs) such as 
extracellular signal-regulating kinase (ERK), c-jun N-terminal protein kinase 
(JNK) and p38 MAPK, leading to caspase-independent apoptosis in cultured 
astrocytes. In view of the previous observation that NO stimulates the activity 
of the Na(+)/Ca(2+) exchanger (NCX), this study examines the involvement of NCX 
in cytotoxicity. The specific NCX inhibitor SEA0400 blocked SNP-induced 
phosphorylation of ERK, JNK and p38 MAPK, and decrease in cell viability. 
SNP-induced phosphorylation of ERK, JNK and p38 MAPK was blocked by removal of 
external Ca(2+), and SNP treatment caused an increase in (45)Ca(2+) influx. This 
increase in (45)Ca(2+) influx was blocked by SEA0400, but not the Ca(2+) channel 
blocker nifedipine. In addition, SNP-induced (45)Ca(2+) influx and cytotoxicity 
were reduced in NCX1-deficient cells which were transfected with NCX1 siRNA. 
Inhibitors of intracellular Ca(2+)-dependent proteins such as calpain and 
calmodulin blocked SNP-induced ERK phosphorylation and decrease in cell 
viability. Furthermore, the guanylate cyclase inhibitor LY83583 and the 
cGMP-dependent protein kinase inhibitor KT5823 blocked SNP-induced cytotoxicity. 
These findings suggest that NCX-mediated Ca(2+) influx triggers SNP-induced 
apoptosis in astrocytes, which may be mediated by a cGMP-dependent pathway.