The effects of four calcium channel blockers (nicardipine, nifedipine, verapamil, and diltiazem) on free radical injury in cultured endothelial cells were studied and compared with those of butylated hydroxytol-uene. When the cultured cells were exposed to a superoxide and hydroxyl radical generating system for up to 60 minutes, lipid peroxidation occurred, and cellular viability decreased by 60% at 30 minutes. Concomitantly, total cellular glutathione decreased by 40%, whereas total protein thiols changed minimally. Preincubation of the cells with each of the calcium blockers (5 and 20 μM) before free radical addition resulted in various degrees of significant protection against cell death, and losses of glutathione correlated significantly (r=0.89,p<0.001). The order of efficacy was nicardipine>nifedipine>verapamil> diltiazem; butylated hydroxytoluene was about fourfold more potent than nicardipine. Because none of the agents affected the level of hydroxyl radicals generated in the aqueous phase, the data suggest that the protective mechanisms were mediated by their lipid antiperoxidative activities, which also prevented the glutathione decrease caused by inhibition of peroxide generation.