Endothelin receptor antagonist attenuates inflammatory response and prolongs the survival time in a neonatal sepsis model.
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.
Goto
Tatenobu
T
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
Hussein
Mohamed Hamed
MH
Kato
Shin
S
Daoud
Ghada Abdel-Hamid
GA
Kato
Takenori
T
Kakita
Hiroki
H
Mizuno
Haruo
H
Imai
Masaki
M
Ito
Tetsuya
T
Kato
Ineko
I
Suzuki
Satoshi
S
Okada
Noriko
N
Togari
Hajime
H
Okada
Hidechika
H
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
D065128:Endothelin Receptor Antagonists