Polymicrobial
sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase. Although studies have suggested that
endothelins (ETs) contribute to the development of
shock after a bolus injection of
endotoxin, little is known about the role of ETs in the transition from the hyperdynamic phase to the hypodynamic phase of
sepsis. To study this, male adult rats were subjected to
sepsis by cecal
ligation and
puncture (CLP) followed by fluid
resuscitation. Plasma levels of ET-1 and ET-2 were measured by radioimmunoassay at 2, 5, 10 h (i.e. the early stage of
sepsis), and 20 h (late stage) following CLP or
sham operation. Tissue levels of ET-1 and ET-2 were determined in the heart, lungs, small intestine, and spleen at 5 h after CLP or
sham operation. In addition,
preproendothelin-1 (precursor of ET-1) gene expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) at 5 h in the heart, lungs, small intestine, spleen, and liver. The results indicate that plasma levels of ET-1 and ET-2 were not different from values of
sham groups at 2 and 20 h, but were significantly higher than the
sham values at 5 and 10 h after CLP. While there were no significant increases in tissue levels of ET-1 and ET-2 at 5 h post-CLP, RT-PCR analysis indicates a significant upregulation of
preproendothelin-1 gene expression in the heart, spleen, and liver (but not in the lungs or small intestine) at 5 h after the onset of
sepsis. These results indicate that the heart, spleen, and liver appear to be important ET-producing organs during the early stage of
sepsis. The lack of significant increases in tissue ET levels could be due to the possibility that the newly converted
peptide is quickly transferred to the bloodstream. Since the hyperdynamic phase of
sepsis occurs at 2-10 h and the hypodynamic phase occurs at 20 h after CLP, the increased plasma levels of ET at 5 and 10 h suggest that mediators other than ETs (such as
adrenomedullin) are responsible for producing the biphasic hemodynamic responses during the progression of polymicrobial
sepsis.