Glycerol-induced augmentation of sensitivity to endotoxin in rats

Combined sepsis and rhabdomyolysis result in a mortality rate much higher than that caused by each process alone. An analogous rat model is obtained by simultaneous i.p. administration of a nonlethal dose of lipopolysaccharide (LPS 0.025 mg/100 g) and a nonlethal i.m. injection of glycerol (1 ml/100 g). The aim of this study was to determine the factors contributing to the high mortality rate in this rat model. The factors examined include: Dehydration, plasma volume expansion, 'immunization' to glycerol, induction of LPS tolerance and the effect of free radicals formed in this model. Neither dehydration nor volume expansion affected mortality. 'Immunization' with glycerol was also not effective. In contradistinction, tolerance to LPS achieved by a daily injection with gradual increasing doses of LPS (from 0.05 mg/100 g to 1 mg/100 g) for 6 days reduced the mortality rate by 60% (P < 0.001). Moreover, decreasing free radical activity using the natural antioxidant (NAO) (5 mg/100 g) reduced mortality rates by 50%. A different antioxidant, dimethylthiourea (DMTU) (50 mg/100 g) failed to reduce mortality rates. This study suggests that the synergism between glycerol and LPS is apparently due to an increase in the rats' sensitivity to endotoxin following glycerol injection. However, endotoxin apparently does not enhance sensitivity to glycerol in the rat. The new antioxidant NAO significantly reduced the high mortality rate.