The molecular mechanisms involved in veratridine-induced chromaffin cell death have been explored.We have found that exposure to veratridine (30 μM, 1 h) produces a delayed cellular death that reaches 55% of the cells 24 h after veratridine exposure. This death has the features of apoptosis as DNA fragmentation can be observed.Calcium ions play an important role in veratridine-induced chromaffin cell death because the cell permeant Ca2+ chelator BAPTA-AM and extracellular Ca2+ removal completely prevented veratridine-induced toxicity.Following veratridine treatment, there is a decrease in mitochondrial function and an increase in superoxide anion production. Veratridine-induced increase in superoxide production was blocked by tetrodotoxin (TTX; 10 μM), extracellular Ca2+ removal and the mitochondrial permeability transition pore blocker cyclosporine A (10 μM).Veratridine-induced death was prevented by different antioxidant treatments including catalase (100 IU ml−1), N-acetyl cysteine (100 μM), allopurinol (100 μM) or vitamin E (50 μM).Veratridine-induced DNA fragmentation was prevented by TTX (10 μM).Veratridine produced a time-dependent increase in caspase activity that was prevented by Ca2+ removal and TTX (10 μM). In addition, calpain and caspases inhibitors partially prevented veratridine-induced death.These results indicate that chromaffin cells share with neurons the molecular machinery involved in apoptotic death and might be considered a good model to study neuronal death during neurodegeneration.