Endothelin (ET), a vasoconstrictive peptide, acts as an anti-apoptotic factor, and endothelin receptor B (ET B receptor) is associated with neuronal survival in the brain. Human group IIA secretory phospholipase A 2 (sPLA 2 -IIA) is expressed in the cerebral cortex after brain ischemia and causes neuronal cell death via apoptosis. In primary cultures of rat cortical neurons, we investigated the effects of an ET B receptor agonist, ET-3, on sPLA 2 -IIA-induced cell death. sPLA 2 -IIA caused neuronal cell death in a concentration- and time-dependent manner. ET-3 significantly prevented neurons from undergoing sPLA 2 -IIA-induced cell death. These agonists reversed sPLA 2 -IIA-induced apoptotic features such as the condensation of chromatin and the fragmentation of DNA. Before cell death, sPLA 2 -IIA potentiated the influx of Ca 2+ into neurons. Blockers of the L-type voltage-dependent calcium channel (L-VSCC) not only suppressed the Ca 2+ influx, but also exhibited neuroprotective effects. As well as L-VSCC blockers, ET-3 significantly prevented neurons from sPLA 2 -IIA-induced Ca 2+ influx. An ET B receptor antagonist, BQ788, inhibited the effects of ET-3. The present cortical cultures contained few non-neuronal cells, indicating that the ET B receptor agonist affected the survival of neurons directly, but not indirectly via non-neuronal cells. In conclusion, we demonstrate that the ET B receptor agonist rescues cortical neurons from sPLA 2 -IIA-induced apoptosis. Furthermore, the present study suggests that the inhibition of L-VSCC contributes to the neuroprotective effects of the ET B receptor agonist.