Previous studies have shown that adrenomedullin (AM), a potent vasodilatory peptide, is upregulated during sepsis. However, it remains unknown whether the increased AM observed under such conditions is solely due to the elevated levels of circulating lipopolysaccharide (LPS). To determine this, an Alzet micro-osmotic pump, containing a low dose of Escherichia coli LPS or vehicle (sterile normal saline), was implanted in the peritoneal cavity of the normal male adult rat. At 10 h after the pump implantation, samples of blood and small intestine were harvested for the determination of AM by radioimmunoassay. In additional groups, rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). LPS binding agent polymyxin B was administrated intramuscularly at 1 h prior to as well as 5 h after the onset of sepsis. At 10 h after CLP or sham-operation, blood and intestinal samples were harvested and levels of AM were then determined. Plasma levels of LPS were also measured by Limulus amebocyte lysate assay. The results indicate that administration of a low dose of LPS via the peritoneal cavity in normal animals (which did not significantly alter cardiac output, blood pressure or heart rate) markedly increased plasma and intestinal levels of AM. In addition, plasma and tissue levels of AM increased significantly at 10 h after CLP. Administration of polymyxin B, however, attenuated the increase in AM levels under such conditions. Similarly, the increased plasma levels of LPS was significantly reduced by polymyxin B during sepsis. These results, taken together, suggest that the upregulated AM observed during polymicrobial sepsis is at least in part due to the increase in circulating levels of endotoxin. © 2001 Elsevier Science B.V. All rights reserved.