We investigated the effects of ghrelin in a rat endotoxic shock model, and also observed the direct role of endotoxin on ghrelin generation in gastric mucosa. About 55% (11/20) of rats treated with lipopolysaccharide (5 mg/kg i.v.) alone died within 24 h of endotoxin injection. However, administration of ghrelin either at the same time as lipopolysaccharide injection (early treatment) or 12 h after lipopolysaccharide injection (late treatment) significantly decreased the mortality rate and ameliorated the hypotension seen in rats with endotoxic shock. Early and late treatment with ghrelin increased markedly the plasma glucose concentration and decreased the plasma lactate concentration. Early treatment with ghrelin attenuated significantly the deficiency in myocardial ATP content, but late treatment with ghrelin had no effect on myocardial ATP content. The plasma ghrelin level was significantly increased in the rats with endotoxin shock, and it increased further after ghrelin administration. Exposure of rat gastric mucosa in vitro to lipopolysaccharide (1.0 to 100 microg/ml) triggered the release of ghrelin from mucosa tissue in a dose- and time-dependent manner, meaning that lipopolysaccharide stimulated directly gastric mucosa to synthesize and secrete ghrelin. The results suggest that ghrelin could have therapeutic value for endotoxic shock.