UP-REGULATION OF A NOVEL POTENT VASODILATORY PEPTIDE ADRENOMEDULLIN DURING POLYMICROBIAL SEPSIS

A large number of studies have been and are being carried out to exami ne the role of nitric oxide in the hyperdynamic and hypodynamic stages of sepsis. It remains unknown, however, whether adrenomedullin (ADM), a novel potent vasodilatory peptide, is up-regulated during hyperdyna mic sepsis and, if so, whether its production is sustained during hypo dynamic sepsis. To determine this, rats were subjected to sepsis by ce cal ligation and puncture (CLP), followed by administration of 3 mL/10 0 g body weight normal saline to these and sham-operated animals. Bloo d samples were taken at 1, 1.5, 2, 5, and 10 h (2-10 h post-CLP repres ents the hyperdynamic stage of sepsis) or at 20 and 30 h after CLP (i. e., the hypodynamic stage). Plasma levels of ADM were measured by radi oimmunoassay. Adrenomedullin gene expression in various tissues was ex amined at 2, 10, or 20 h after CLP by reverse transcription-polymerase chain reaction (RT-PCR). The results indicated that plasma levels of ADM did not increase at 1 and 1.5 h after CLP but increased significan tly at 2 h after the onset of sepsis. Moreover, circulating ADM increa sed progressively at 5-20 h and remained elevated at 30 h after CLP. T he increased levels of plasma ADM during sepsis were correlated with u p-regulation of ADM mRNA in the small intestine, left ventricle, and t horacic aorta. In contrast, ADM gene expression in renal and hepatic t issues was not significantly altered following the onset of sepsis. Th e association between the up-regulated ADM and the occurrence of hyper dynamic circulation during the early stage of sepsis (both occur at 2 h after CLP) may indicate a possible cause and effect relationship bet ween the two events. Since we have previously shown that ADM-induced v ascular relaxation decreased at 20 h after CLP, it appears that the do wn-regulation of ADM receptors may be responsible for the transition f rom the hyperdynamic stage to the hypodynamic stage of sepsis.