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Endothelin receptor antagonist attenuates inflammatory response and prolongs the survival time in a neonatal sepsis model

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Abstract

Purpose

To evaluate effects of endothelin receptor antagonist ETR-P1/fl in a neonatal sepsis model.

Method

Eighteen anesthetized and mechanically ventilated 3-day-old piglets were divided into three groups. Six piglets received cecal ligation and perforation (CLP group). Six piglets were administrated a continuous infusion of ETR-P1/fl (0.05 mg/kg/h), an antisense homology box-derived peptide with an endothelin A receptor antagonist effect, starting 30 min after CLP (ETR-P1/fl group). Six piglets acted as the sham group. Mean arterial pressure (MAP), heart rate, cardiac output, arterial blood gas, body temp (BT), serum nitrite and nitrate (NOx), tumor necrosis factor (TNF)-α, and high-mobility group box 1 (HMGB-1) were measured before CLP and at 1, 3, 6, and 9 h after CLP.

Results

Cecal ligation and perforation exposure evoked a state of shock and showed deteriorated cardiac output, pulmonary hypertension, decreased MAP, low oxygen saturation, and base excess (BE) with elevated TNF-α, NOx, and HMGB1. ETR-P1/fl administration resulted in higher MAP at 6 and 9 h after CLP, less negative BE, lower mean pulmonary arterial pressure (mPAP)/MAP ratio at 9 h after CLP, and lower TNF-α, NOx, and HMGB-1 compared to the CLP group. BT showed no differences between the groups. Survival time in the ETR-P1/fl group was longer than in the CLP group (18.9 ± 2.3 h vs. 9.0 ± 0.8 h, p < 0.01).

Conclusions

ETR-P1/fl treatment significantly attenuated the elevation of NOx, TNF-α, and HMGB-1, which improved the systemic hypotension, pulmonary hypertension, and blood gases, thereby causing improvement of survival time in a progressive neonatal sepsis CLP model.

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Correspondence to Tatenobu Goto.

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Goto, T., Hussein, M.H., Kato, S. et al. Endothelin receptor antagonist attenuates inflammatory response and prolongs the survival time in a neonatal sepsis model. Intensive Care Med 36, 2132–2139 (2010). https://doi.org/10.1007/s00134-010-2040-0

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Keywords

  • Newborn
  • Septic shock
  • Cytokines
  • Nitric oxide
  • Antisense homology box-derived peptide