Various beneficial effects of calcium channel blockers on cell and organ function following endotoxic shock, organ ischemia, and reperfusion have been reported; however, it is not known whether these agents have any salutary or deleterious effects on immune responses after low-flow conditions. Therefore, the aim of this study was to determine (a) the effect of hemorrhage on lymphocyte IL-2, IL-3, IL-6, and IFN-γ synthesis, and (b) whether diltiazem has any salutary or adverse effects on these parameters when administered following hemorrhage and resuscitation. To study this, C3H/HeN mice were bled to a mean blood pressure of 35 mm Hg, maintained at that level for 60 min, and resuscitated with shed blood plus twice that volume of Ringer's lactate. Immediately following resuscitation mice received either diltiazem (2400, 800, or 400 μg/kg body wt), or an equivalent volume of saline. The mice were sacrificed 24 hr later, splenic lymphocytes were obtained, and their capacity to produce lymphokines was assessed. The results indicated that in the vehicle-treated animals, hemorrhage significantly decreased (P < 0.05) IL-2, IL-3, IL-6, and IFN-γ synthesis by 82 ± 19%, 64 ± 28%, 71 ± 11%, and 86 ± 14%, respectively. However, diltiazem (400 but not 2400 μg/kg) treatment after hemorrhage restored lymphocyte capacity to produce IL-2, IL-3, IL-6, and IFN-γ (P < 0.05). Additional groups of animals were subjected to sepsis by cecal ligation and puncture 3 days following hemorrhage. The results indicated that 400 μg/kg diltiazem significantly improved (P < 0.05) the survival of animals following hemorrhage and sepsis (42.9% with vs 0% without diltiazem) to rates comparable to those seen in nonhemorrhaged controls (35.7%). Thus, the use of diltiazem may offer a new therapeutic modality in the treatment of immunodepression and for decreasing the susceptibility to sepsis following shock and trauma. © 1991.