title: Endothelin receptor antagonist attenuates inflammatory response and prolongs the survival time in a neonatal sepsis model.
abstract: OBJECTIVE
  To evaluate effects of endothelin receptor antagonist ETR-P1/fl in a neonatal sepsis model.
  
  
  METHODS
  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.
authors.affiliation: Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan. gototate@gmail.com
authors.forename: Tatenobu
authors.initials: T
authors.lastname: Goto
authors.forename: Mohamed Hamed
authors.initials: MH
authors.lastname: Hussein
authors.forename: Shin
authors.initials: S
authors.lastname: Kato
authors.forename: Ghada Abdel-Hamid
authors.initials: GA
authors.lastname: Daoud
authors.forename: Takenori
authors.initials: T
authors.lastname: Kato
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakita
authors.forename: Haruo
authors.initials: H
authors.lastname: Mizuno
authors.forename: Masaki
authors.initials: M
authors.lastname: Imai
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ito
authors.forename: Ineko
authors.initials: I
authors.lastname: Kato
authors.forename: Satoshi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Noriko
authors.initials: N
authors.lastname: Okada
authors.forename: Hajime
authors.initials: H
authors.lastname: Togari
authors.forename: Hidechika
authors.initials: H
authors.lastname: Okada
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D007249:Inflammation / Q000517:prevention & control*; D018805:Sepsis / Q000401:mortality / Q000517:prevention & control*; D015996:Survival Rate; D013552:Swine; D013997:Time Factors
chemical_list: D065128:Endothelin Receptor Antagonists