The nitric oxide (NO) donors, sodium nitroprusside (SNP), 1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium+ ++-1,2-diolate] (DETA NONOate), and S-nitroso-N-acetyl-D,L-penicillamine (SNAP) produce a dose-dependent increase in cell death in a catecholaminergic cell line (CATH.a) derived from the central nervous system. Cell death is associated with a decrease in mitochondrial membrane potential. Dopamine also induced cell death of CATH.a cells and this was potentiated by concentrations of SNP which alone did not produce cell death. Hemoglobin, a scavenger of NO radicals, blocked SNP- and SNAP-induced cell death. Catalase and superoxide dismutase, enzymes that metabolize H2O2 and superoxide, respectively, did not inhibit SNP- or SNAP-induced cell death. These data indicate that NO donors produce cell death in CATH.a cells through a mechanism related to the production of NO and the loss of the mitochondrial membrane potential but unrelated to the production of H2O2.