1. Using SEA0400, a potent and selective inhibitor of the Na+-Ca2+ exchanger 
(NCX), we examined whether NCX is involved in nitric oxide (NO)-induced 
disturbance of endoplasmic reticulum (ER) Ca2+ homeostasis followed by apoptosis 
in cultured rat microglia. 2. Sodium nitroprusside (SNP), an NO donor, decreased 
cell viability in a dose- and time-dependent manner with apoptotic cell death in 
cultured microglia. 3. Treatment with SNP decreased the ER Ca2+ levels as 
evaluated by measuring the increase in cytosolic Ca2+ level induced by exposing 
cells to thapsigargin, an irreversible inhibitor of ER Ca2+-ATPase. 4. The 
treatment with SNP also increased mRNA expression of CHOP and GPR78, makers of 
ER stress. 5. SEA0400 at 0.3-1.0 microM protected microglia against SNP-induced 
apoptosis. 6. SEA0400 blocked not only the SNP-induced decrease in ER Ca2+ 
levels but also SNP-induced increase in CHOP and GRP78 mRNAs. 7. SEA0400 did not 
affect capacitative Ca2+ entry in the presence and absence of SNP. 8. SNP 
increased Na+-dependent 45Ca2+ uptake and this increase was blocked by SEA0400. 
9. These results suggest that SNP induces apoptosis via the ER stress pathway 
and SEA0400 attenuates SNP-induced apoptosis via suppression of the ER stress in 
cultured microglia. Our findings imply that NCX plays a role in ER Ca2+ 
depletion under pathological conditions.