Adrenomedullin (AM), a potent vasodilatory peptide, has recently been reported to be involved in the altered cardiovascular responses under various pathophysiological conditions. Although the increase in plasma AM levels is associated with upregulation of AM gene expression in various tissues, it remains unknown whether the gut is an important source of AM release under such conditions. To determine this, adult male rats were subjected to sepsis by cecal ligation and puncture (CLP) followed by fluid resuscitation. Systemic and portal blood samples were collected simultaneously at 10 and 20 h after CLP or sham operation. A portion of the jejunum was also harvested. Plasma and tissue levels of AM were then determined by RIA. The localization of AM in the intestinal tissue was examined using immunohistochemistry. In an additional group of normal rats, synthetic rat AM (8.5 μg/kg body wt) was infused for 15 min at a constant rate via the portal vein (which produces a similar level of AM as observed during sepsis). Cardiac output, stroke volume, total peripheral resistance, and microvascular blood flow in various organs were determined before and 30 min after AM administration. The results indicate that AM levels in portal blood were significantly higher than in systemic blood at 10 and 20 h after CLP. Intestinal AM was also markedly elevated. Immunohistochemical visualization shows that AM immunostainings were localized in the mucosa, submucosa, and intestinal nerve fibers, and they were increased at 10-20 h post-CLP. Because AM-immunopositive nerve fibers increase in the gut during sepsis, a nerve pathway may be involved in the regulation of vascular reactivity by this peptide. Moreover, intraportal administration of AM increased cardiac output, stroke volume, and microvascular blood flow in the liver, kidney, small intestine, and spleen. In contrast, total peripheral resistance was significantly reduced. Thus the gut plays an important role in increasing the levels of circulating AM during the progression of sepsis. Gut-derived AM appears to be a major factor in initiating the hyperdynamic response after the onset of sepsis.