Sepsis is the systemic inflammatory response resulting from serious infection and is the most common cause of death in intensive care units. Intracellular free calcium concentration ([Ca2+]i) is an important regulator of numerous cellular processes and when increased excessively may act as a potent cellular toxin. To determine if [Ca2+]i is responsible for the major metabolic changes which are hallmarks of sepsis, we examined if sodium dantrolene, a drug which decreases release of calcium from sarcoplasmic reticulum, affected the metabolic abnormalities in plasma and epitrochlearis muscles of rats made septic by cecal ligation and perforation. Dantrolene when added in vitro or when given in vivo decreases many of the metabolic hallmarks of sepsis--i.e., muscle protein breakdown approximately 30%, muscle glucose transport approximately 38%, muscle lactate formation approximately 28%, and plasma lactate approximately 29% (P < 0.05). In addition, we examined the ability of dantrolene to improve survival in a mouse model of endotoxemia. Dantrolene caused > 2-fold improvement in survival when it was administered concurrently with endotoxin (54% vs. 20% survival in dantrolene-treated and control mice, respectively (P < 0.001). Our results are consistent with the hypothesis that an increase in [Ca2+]i plays an important role in the metabolic abnormalities which occur during sepsis and that dantrolene administration may be an effective therapeutic strategy.