Aims: 

The early hyperdynamic phase of sepsisleads to disturbances in the balance between the the oxygen delivery (DO₂) and the oxigen consumption (VO₂) of the cells. This is followed by circular insufficiency as the hallmark of the hypodynamic phase. The background of this complex pathophysiological process is still controversial but there are already evidences for the important role of the cytokine-induced endothelin release and the systemic activation of the endothelin-A receptors (ETAr). In our present study, we evaluated the efficiency of the early use of selective ETAr antagonism in a clinically relevant rat model of sepsis.

Methods: 

Anesthetized SPRD rats were subjected to fecal peritonitis (n=8; 0.6 g/kg i.p. autofaeces), and ETAr antagonist-treated peritonitis (n=8), or sham-operated (i.p. saline, n=8) groups. The ETAr antagonist ETR-p1/fl peptid (100 nmol/kg, iv.) was given 17 hr after the induction of sepsis. Invasive hemodynamic monitoring was started with regular blood gas analyses between the 16–20 hr of the insult to calculate VO₂-DO₂ values. Superoxide (SOX), xanthine oxidase (XO) activity and nitric oxid (NOx) production were determined from small intestine biopsies, whereas myeloperoxidase (MPO) activity was measured from lung biopsy at the end of the experiments.

Results: 

The septic reaction was accompanied by significant elevation of cardiac output, DO₂ values and activation of SOX, XO and MPO, while the VO₂ values decreased. The ETR-p1/fl peptide treatment augmented the DO₂-VO₂ changes and increased NOx levels, and in addition inhibited the rise of SOX, XO, and MPO activities.

Conclusion: 

The inhibition of the vasocontrictive ETAr is leading to a maintained cellular oxygen dynamics and in paralell reduces the activation of the inflammatory cascade mechanisms.

Support: 

ETT 442/2009; TÁMOP4.2.1; TÁMOP-4.2.2; TÉT JP 16/09