We examined the role of intracellular Ca 2 + in the mechanism of the preventive effects of the Ca 2 + -channel blocker verapamil against lipoprotein disturbances during tumor necrosis factor (TNFα)-induced shock syndrome. The heparin-releasable lipoprotein lipase (LPL) activity in plasma of TNFα (5x10 4 units/mouse, i.v.)-injected mice was markedly lower at 4 h post-intoxication than in the controls. In mice treated with verapamil (10 mg/kg, s.c.), the activity of LPL 4 h after TNFα injection was significantly higher than in mice treated with TNFα alone. On the other hand, on polyacrylamide gel disk electrophoresis, very low density lipoprotein (VLDL) and high density lipoprotein (HDL) fractions in the sera of TNFα-injected mice were increased and reduced, respectively, relative to the controls. The administration of verapamil clearly prevented the lipoprotein damage arising from TNFα challenge. We investigated whether verapamil could suppress TNFα generation in endotoxin-treated J774A.1 cells. Treatment with verapamil (30 μM) markedly inhibited endotoxin (1 μg/ml)-induced TNFα production in these cells. These findings suggest that the concentration of intracellular Ca 2 + may contribute to the extent of lipoprotein disturbances in plasma, which results from LPL suppression in TNFα-induced shock syndrome. Verapamil may, therefore, protect against some of the various disturbances caused by changes in Ca 2 + mobilization through its ability to inhibit TNFα production in septic shock.